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Zheng T, Huang KY, Tang XD, Wang FY, Lv L. Endoplasmic reticulum stress in gut inflammation: Implications for ulcerative colitis and Crohn’s disease. World J Gastroenterol 2025; 31:104671. [DOI: 10.3748/wjg.v31.i13.104671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/20/2025] [Accepted: 03/13/2025] [Indexed: 04/02/2025] Open
Abstract
Eukaryotic cells contain the endoplasmic reticulum (ER), a prevalent and intricate membranous structural system. During the development of inflammatory bowel disease (IBD), the stress on the ER and the start of the unfolded protein response are very important. Some chemicals, including 4μ8C, small molecule agonists of X-box binding protein 1, and ISRIB, work on the inositol-requiring enzyme 1, turn on transcription factor 6, and activate protein kinase RNA-like ER kinase pathways. This may help ease the symptoms of IBD. Researchers investigating the gut microbiota have discovered a correlation between ER stress and it. This suggests that changing the gut microbiota could help make new medicines for IBD. This study looks at how ER stress works and how it contributes to the emergence of IBD. It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.
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Affiliation(s)
- Ting Zheng
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Kai-Yue Huang
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xu-Dong Tang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Feng-Yun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Lin Lv
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
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2
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Liu T, Wang M, Li L, Wu T, Ji H, Zheng M, Tang L, Gan W, Wen Z, Yuan F. Mitophagy drives maldifferentiation of tissue-resident memory T cells in patients with rheumatoid arthritis. Scand J Rheumatol 2025; 54:69-78. [PMID: 39544132 DOI: 10.1080/03009742.2024.2420432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 10/21/2024] [Indexed: 11/17/2024]
Abstract
OBJECTIVE To investigate the function of mitophagy in instructing T-cell differentiation of patients with rheumatoid arthritis (RA). METHOD The mRNA and protein levels of optic atrophy protein-1 were detected in T cells from 94 RA patients and 37 age- and sex-matched healthy individuals by quantitative polymerase chain reaction and Western blotting. The impact of mitophagy on the differentiation of T cells was determined by flow cytometry. The therapeutic effect of targeting mitophagy was explored in humanized RA chimeras. RESULTS Our study showed that T cells exerted high levels of mitophagy in RA patients. Since multiple T-cell subtypes play crucial roles in RA, we determined that mitophagy had a significant impact on the differentiation of tissue-resident memory T (Trm) cells, but not Th1 or Th17 cells. Importantly, we demonstrated that inhibiting mitophagy significantly reduced the number of Trm cells and downregulated inflammatory responses, as evidenced by diminished levels of T cell receptor β, interferon-γ, and interleukin-17A, in the humanized RA chimeras. CONCLUSIONS Mitophagy is elevated in RA T cells, leading to maldifferentiation of Trm cells in RA patients. Since these findings were obtained from clinical patients, mitophagy may be a potential therapeutic target for RA treatment.
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Affiliation(s)
- T Liu
- Department of Rheumatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, PR China
| | - M Wang
- Division of Research Center, Suzhou Blood Center, Suzhou, PR China
| | - L Li
- The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, PR China
- Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, PR China
| | - T Wu
- The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, PR China
- Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, PR China
| | - H Ji
- The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, PR China
- Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, PR China
| | - M Zheng
- The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, PR China
- Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, PR China
| | - L Tang
- Division of Research Center, Suzhou Blood Center, Suzhou, PR China
| | - W Gan
- Department of Pathology, The Fourth Affiliated Hospital of Soochow University, Suzhou, PR China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, PR China
| | - Z Wen
- The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, PR China
- Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, PR China
| | - F Yuan
- Department of Rheumatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, PR China
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3
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Peng S, Zhao Y, Jiang W, Long Y, Hu T, Li M, Hu J, Shen Y. MAPK signaling mediated intestinal inflammation induced by endoplasmic reticulum stress and NOD2. Mol Cell Biochem 2025:10.1007/s11010-025-05212-3. [PMID: 39806198 DOI: 10.1007/s11010-025-05212-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Endoplasmic reticulum (ER) stress is crucially involved in inflammatory bowel disease (IBD), but the mechanisms remain incompletely understood. This study aimed to elucidate how ER stress promotes inflammation in IBD. ER stress marker Grp78 and NOD2 in colon tissues of Crohn's disease (CD) patients and IBD model mice were detected by immunohistochemical analysis. THP-1 cells were exposed to ER stress and the expression of NOD2 and inflammatory cytokines was detected by PCR. We found that ER stress markers Grp78 and NOD2 were upregulated in intestinal tissues of CD patients and in THP-1 cells exposed to ER stress. ER stress inhibitor reduced Grp78 and NOD2 expression in colitis model mice and alleviated colitis. ER stress inducer cooperated with NOD2 ligand MDP to upregulate TNF-α, IL-8 and IL-1β, and activate MAPK signaling in THP-1 cells. Moreover, inhibitors of MAPK signaling led to the downregulation of IL-1β, IL-8 and TNF-α in THP-1 cells stimulated by ER stress inducer and MDP. In conclusion, ER stress upregulates NOD2 and promotes inflammation in IBD, at least partially due to the activation of MAPK pathway.
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Affiliation(s)
- Siyuan Peng
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yan Zhao
- Department of Pathology, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Wang Jiang
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yan Long
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Tian Hu
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Mengling Li
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yueming Shen
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China.
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Sun S, Hodel M, Wang X, De Vicente J, Haritunians T, Debebe A, Hung CT, Ma C, Malique A, Nguyen HN, Agam M, Maloney MT, Goo MS, Kluss JH, Mishra R, Frein J, Foster A, Ballentine S, Pandey U, Kern J, Yang S, Mengesha E, Balasubramanian I, Arguello A, Estrada AA, Gao N, Peter I, McGovern DPB, Henry AG, Stappenbeck TS, Liu TC. Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction. Sci Immunol 2024; 9:eadi7907. [PMID: 39514635 PMCID: PMC11730131 DOI: 10.1126/sciimmunol.adi7907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/26/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024]
Abstract
LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.
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Affiliation(s)
- Shengxiang Sun
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Miki Hodel
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Xiang Wang
- Denali Therapeutics, South San Francisco, CA 94080, USA
| | | | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Anketse Debebe
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount-Sinai, New York, NY 10029, USA
| | - Chen-Ting Hung
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Changqing Ma
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Atika Malique
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | | | - Maayan Agam
- Denali Therapeutics, South San Francisco, CA 94080, USA
| | | | - Marisa S. Goo
- Denali Therapeutics, South San Francisco, CA 94080, USA
| | | | - Richa Mishra
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jennifer Frein
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Amanda Foster
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Samuel Ballentine
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Uday Pandey
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Justin Kern
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Shaohong Yang
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Emebet Mengesha
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | | | | | | | - Nan Gao
- Department of Biological Sciences, Rutgers, State University of New Jersey, Newark, NJ 07102, USA
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount-Sinai, New York, NY 10029, USA
| | - Dermot P. B. McGovern
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | | | - Thaddeus S. Stappenbeck
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Li M, Zhao Y, Zhang J, Jiang W, Peng S, Hu J, Shen Y. Deubiquitinase USP14 is upregulated in Crohn's disease and inhibits the NOD2 pathway mediated inflammatory response in vitro. Eur J Histochem 2024; 68:4101. [PMID: 39252535 PMCID: PMC11445697 DOI: 10.4081/ejh.2024.4101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 08/16/2024] [Indexed: 09/11/2024] Open
Abstract
The nucleotide binding oligomerization domain containing 2 (NOD2) protein and its ligand N-acetyl muramyl dipeptide (MDP) are crucially involved in Crohn's disease (CD). However, the mechanism by which NOD2 signaling is regulated in CD patients remains unclear. Ubiquitin specific protease (USP14) is a deubiquitylase that plays an important role in immunity. This study aimed to investigate the mechanism by which UPS14 regulates NOD2 induced inflammatory response in CD and inflammatory bowel diseases (IBD). Our results showed that USP14 protein and mRNA levels in intestinal tissues of CD patients were significantly higher than those in healthy controls. In addition, USP14 was upregulated in IBD mouse model. While treatment with MDP, TNF-α or the Toll-like receptor 1/2 agonist Pam3CSK4 all led to significantly higher mRNA levels of TNF-α, IL-8 and IL-1β in THP-1 cells, pretreatment with USP14 inhibitor IU1 could stimulate further upregulation of TNF-α, IL-8 and IL-1β. In particular, MDP promoted the activation of JNK, ERK1/2 and p38 as well as NF-kB in THP-1 cells, and IU1 significantly enhanced the MDP-induced activation of these proteins without effects on USP14 protein level. Furthermore, the JNK inhibitor sp600125, ERK1/2 inhibitor U0126 or P38 MAPK inhibitor PD169316 significantly decreased the mRNA levels of TNF-α, IL-8 and IL-1β in THP-1 cells stimulated by both IU1 and MDP. In conclusion, our findings suggest that USP14 could inhibit MDP-induced activation of MAPK signaling and the inflammation response involved in IBD, and that USP14 is a potential therapeutic target for IBD.
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Affiliation(s)
- Mengling Li
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Yan Zhao
- Department of Pathology, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Jiayi Zhang
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Wang Jiang
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Siyuan Peng
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
| | - Yueming Shen
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, Changsha, Hunan.
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Jauregui W, Abarca YA, Ahmadi Y, Menon VB, Zumárraga DA, Rojas Gomez MC, Basri A, Madala RS, Girgis P, Nazir Z. Shared Pathophysiology of Inflammatory Bowel Disease and Psoriasis: Unraveling the Connection. Cureus 2024; 16:e68569. [PMID: 39364475 PMCID: PMC11449469 DOI: 10.7759/cureus.68569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2024] [Indexed: 10/05/2024] Open
Abstract
Psoriasis (PS) and inflammatory bowel disease (IBD) are immune-mediated chronic conditions that share pathophysiological processes, including immune system dysfunction, microbiome dysbiosis, and inflammatory pathways. These pathways result in increased turnover of epithelial cells and compromised barrier function. The assessment of the literature suggests that immunopathogenic mechanisms, such as tumor necrosis factor (TNF)-α signaling and IL-23/IL-17 axis dysregulation, are shared by PS and IBD. Clinical characteristics and diagnostic approaches overlap significantly, and advances in biomarker identification benefit both conditions. Current treatments, namely biologics that target TNF-α, IL-17, and IL-23, show promising results in decreasing inflammation and controlling symptoms. Precision medicine approaches are prioritized in prospective therapeutic procedures to tailor pharmaceuticals based on specific biomarkers, perhaps improving outcomes and minimizing side effects. This study thoroughly examines and evaluates the body of research on PS and IBD. Several papers were examined to compile data on clinical features, diagnosis, therapies, pathophysiology, epidemiology, and potential future therapeutic developments. The selection of articles was based on three methodological qualities: relevance and addition to the knowledge of IBD and PS. The retrieved data were combined to provide a coherent summary of the state of the knowledge and to spot new trends. The overview of the latest studies demonstrates that both PS and IBD share pathophysiological foundations and therapeutic approaches. With a spotlight on particular biomarkers, advances in precision medicine provide a promising path toward enhancing therapeutic effectiveness and minimizing side effects.
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Affiliation(s)
- Walter Jauregui
- General Medicine, Universidad Nacional Autónoma de Honduras, Tegucigalpa, HND
| | - Yozahandy A Abarca
- Internal Medicine, Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Mexico City, MEX
| | - Yasmin Ahmadi
- School of Medicine, Royal College of Surgeons in Ireland - Medical University of Bahrain, Muharraq, BHR
| | - Vaishnavi B Menon
- Internal Medicine, Sri Ramachandra Institute of Higher Education and Research, Chennai, IND
| | | | | | - Aleeza Basri
- Internal Medicine, Liaquat University of Medical and Health Sciences, Hyderabad, PAK
| | | | - Peter Girgis
- Internal Medicine, Ross University School of Medicine, Bridgetown, BRB
| | - Zahra Nazir
- Internal Medicine, Combined Military Hospital, Quetta, PAK
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7
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Zhang D, Liu J, Lv L, Chen X, Qian Y, Zhao P, Zhang Q, Chen Y, Qian H. Total flavone of Abelmoschus manihot regulates autophagy through the AMPK/mTOR signaling pathway to treat intestinal fibrosis in Crohn's disease. J Gastroenterol Hepatol 2024; 39:1586-1596. [PMID: 38803139 DOI: 10.1111/jgh.16560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 03/06/2024] [Accepted: 03/25/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND AND AIM Drug therapy is the treatment of choice for Crohn's disease because it effectively controls or prevents intestinal inflammation. The purpose was to research the molecular mechanism of the total flavones of Abelmoschus manihot (TFA) on intestinal fibrosis in Crohn's disease. METHODS A 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model and IGF-1-treated intestinal fibroblasts were established. Then, TFA, 3-MA, and compound C were used treatments. Hematoxylin and eosin, Masson, and Picrosirius red staining were performed to observe the colon tissue. Immunohistochemical staining was used to detect α-SMA expression. Flow cytometry, CCK8, wound healing, and Transwell assays were conducted to determine apoptosis, proliferation, invasion, and migration. Col1a1 and Col3a1 levels were detected using quantitative polymerase chain reaction. Proteins related to autophagy and apoptosis were detected using western blotting. RESULTS TFA treated intestinal fibrosis in chronic Crohn's disease. Colon length was the shortest in the ethanol + TNBS group, and TFA treatment significantly improved the situation. Intestinal fibrosis and the percentage of collagen area decreased after TFA treatment. TFA reduced fibrosis by enhancing autophagy stimulation, whereas an autophagy inhibitor reversed the TFA effect. TFA also inhibited migration, proliferation, and collagen synthesis in intestinal fibroblasts. Moreover, it enhanced autophagy and apoptosis of intestinal fibroblasts. TFA upregulated p-AMPK expression and decreases p-mTOR levels. Compound C partially rescued the effect of TFA, indicating that TFA affected intestinal fibroblasts via the AMPK/mTOR pathway in vitro and in vivo. TFA also downregulated Col1a1 and Col3a1 expression. CONCLUSION TFA regulates autophagy through AMPK/mTOR signaling pathway to treat intestinal fibrosis, which may provide a new therapy for Crohn's disease treatment.
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Affiliation(s)
- Dan Zhang
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiali Liu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lei Lv
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xiaopin Chen
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yunzhi Qian
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Peizhen Zhao
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qiaofeng Zhang
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yugen Chen
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Haihua Qian
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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Zhao J, Duan L, Li J, Yao C, Wang G, Mi J, Yu Y, Ding L, Zhao Y, Yan G, Li J, Zhao Z, Wang X, Li M. New insights into the interplay between autophagy, gut microbiota and insulin resistance in metabolic syndrome. Biomed Pharmacother 2024; 176:116807. [PMID: 38795644 DOI: 10.1016/j.biopha.2024.116807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/20/2024] [Accepted: 05/20/2024] [Indexed: 05/28/2024] Open
Abstract
Metabolic syndrome (MetS) is a widespread and multifactorial disorder, and the study of its pathogenesis and treatment remains challenging. Autophagy, an intracellular degradation system that maintains cellular renewal and homeostasis, is essential for maintaining antimicrobial defense, preserving epithelial barrier integrity, promoting mucosal immune response, maintaining intestinal homeostasis, and regulating gut microbiota and microbial metabolites. Dysfunctional autophagy is implicated in the pathological mechanisms of MetS, involving insulin resistance (IR), chronic inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, with IR being a predominant feature. The study of autophagy represents a valuable field of research with significant clinical implications for identifying autophagy-related signals, pathways, mechanisms, and treatment options for MetS. Given the multifactorial etiology and various potential risk factors, it is imperative to explore the interplay between autophagy and gut microbiota in MetS more thoroughly. This will facilitate the elucidation of new mechanisms underlying the crosstalk among autophagy, gut microbiota, and MetS, thereby providing new insights into the diagnosis and treatment of MetS.
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Affiliation(s)
- Jinyue Zhao
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Liyun Duan
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Jiarui Li
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Chensi Yao
- Molecular Biology Laboratory, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Guoqiang Wang
- The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Jia Mi
- The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Yongjiang Yu
- The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Lu Ding
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Yunyun Zhao
- The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Guanchi Yan
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Jing Li
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Zhixuan Zhao
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China
| | - Xiuge Wang
- The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China.
| | - Min Li
- Molecular Biology Laboratory, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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9
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Fan X, Lu Q, Jia Q, Li L, Cao C, Wu Z, Liao M. Prevotella histicola ameliorates DSS-induced colitis by inhibiting IRE1α-JNK pathway of ER stress and NF-κB signaling. Int Immunopharmacol 2024; 135:112285. [PMID: 38762922 DOI: 10.1016/j.intimp.2024.112285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 05/07/2024] [Accepted: 05/14/2024] [Indexed: 05/21/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal inflammation regulated by intricate mechanisms. Recently, prebiotics is considered as promising nutritional strategy for the prevention and treatment of IBD. Prevotella histicola (P. histicola), an emerging probiotic, possesses apparently anti-inflammatory bioactivity. However, the role and underlying mechanism of P. histicola on IBD remain unclear. Hence, we probe into the effect of P. histicola on dextran sulfate sodium (DSS)-induced colitis and clarified the potential mechanism. Our results revealed that DSS-induced colonic inflammatory response and damaged epithelial barrier in mice were attenuated by oral administration of P. histicola. Moreover, supplementary P. histicola significantly enriched short-chain fatty acid (SCFA)-producing bacteria (Lactobacillus, and Bacillus) and reduced pathogenic bacteria (Erysipelotrichaceae, Clostridium, Bacteroides) in DSS-induced colitis. Notably, In DSS-treated mice, endoplasmic reticulum stress (ERS) was persistently activated in colonic tissue. Conversely, P. histicola gavage suppressed expansion of endoplasmic reticulum, downregulated PERK-ATF4-CHOP and IRE1α-JNK pathway. In vitro, the P. histicola supernatant eliminated LPS-induced higher production of pro-inflammatory cytokines regulated by NF-κB and impairment of epithelial barrier by inhibiting IRE1α-JNK signaling in Caco-2 cell. In summary, our study indicated that P. histicola mitigated DSS-induced chronic colitis via inhibiting IRE1α-JNK pathway and NF-κB signaling. These findings provide the new insights into the promotion of gut homeostasis and the application potential of P. histicola as a prebiotic for IBD in the future.
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Affiliation(s)
- Xiaoxiao Fan
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qiuxia Lu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qing Jia
- Laboratory Animal Resources Center, Wenzhou Medical University, Wenzhou, China
| | - Liangqiong Li
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Cong Cao
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ziniu Wu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Min Liao
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
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10
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Kong L, Cao Y, He Y, Zhang Y. Role and molecular mechanism of NOD2 in chronic non-communicable diseases. J Mol Med (Berl) 2024; 102:787-799. [PMID: 38740600 DOI: 10.1007/s00109-024-02451-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
Nucleotide-binding oligomerization domain containing 2 (NOD2), located in the cell cytoplasm, is a pattern recognition receptor belonging to the innate immune receptor family. It mediates the innate immune response by identifying conserved sequences in bacterial peptide glycans and plays an essential role in maintaining immune system homeostasis. Gene mutations of NOD2 lead to the development of autoimmune diseases such as Crohn's disease and Blau syndrome. Recently, NOD2 has been shown to be associated with the pathogenesis of diabetes, cardiac-cerebral diseases, and cancers. However, the function of NOD2 in these non-communicable diseases (CNCDs) is not well summarized in reviews. Our report mainly discusses the primary function and molecular mechanism of NOD2 as well as its potential clinical significance in CNCDs.
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Affiliation(s)
- Lingjun Kong
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong, People's Republic of China
| | - Yanhua Cao
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong, People's Republic of China
| | - Yanan He
- Gamma Knife Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People's Republic of China
| | - Yahui Zhang
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong, People's Republic of China.
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11
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Wang M, Wang Z, Li Z, Qu Y, Zhao J, Wang L, Zhou X, Xu Z, Zhang D, Jiang P, Fan B, Liu Y. Targeting programmed cell death in inflammatory bowel disease through natural products: New insights from molecular mechanisms to targeted therapies. Phytother Res 2024. [PMID: 38706097 DOI: 10.1002/ptr.8216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 03/14/2024] [Accepted: 04/11/2024] [Indexed: 05/07/2024]
Abstract
Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.
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Affiliation(s)
- Mengjie Wang
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhiyuan Wang
- People's Hospital of Zhengzhou, Zhengzhou, China
| | - Zhichao Li
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuan Qu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiting Zhao
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Wang
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xinpeng Zhou
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ziqi Xu
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Di Zhang
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ping Jiang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Bing Fan
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ying Liu
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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12
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Jia K, Shen J. Transcriptome-wide association studies associated with Crohn's disease: challenges and perspectives. Cell Biosci 2024; 14:29. [PMID: 38403629 PMCID: PMC10895848 DOI: 10.1186/s13578-024-01204-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 02/04/2024] [Indexed: 02/27/2024] Open
Abstract
Crohn's disease (CD) is regarded as a lifelong progressive disease affecting all segments of the intestinal tract and multiple organs. Based on genome-wide association studies (GWAS) and gene expression data, transcriptome-wide association studies (TWAS) can help identify susceptibility genes associated with pathogenesis and disease behavior. In this review, we overview seven reported TWASs of CD, summarize their study designs, and discuss the key methods and steps used in TWAS, which affect the prioritization of susceptibility genes. This article summarized the screening of tissue-specific susceptibility genes for CD, and discussed the reported potential pathological mechanisms of overlapping susceptibility genes related to CD in a certain tissue type. We observed that ileal lipid-related metabolism and colonic extracellular vesicles may be involved in the pathogenesis of CD by performing GO pathway enrichment analysis for susceptibility genes. We further pointed the low reproducibility of TWAS associated with CD and discussed the reasons for these issues, strategies for solving them. In the future, more TWAS are needed to be designed into large-scale, unified cohorts, unified analysis pipelines, and fully classified databases of expression trait loci.
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Affiliation(s)
- Keyu Jia
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Nephrology department, Shanghai Jiao Tong University, 1058 Huanzhen Northroad, Shanghai, 200444, China
| | - Jun Shen
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Nephrology department, Shanghai Jiao Tong University, 1058 Huanzhen Northroad, Shanghai, 200444, China.
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Research Center, Ren Ji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China.
- NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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13
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Metwaly A, Haller D. The TNF∆ARE Model of Crohn's Disease-like Ileitis. Inflamm Bowel Dis 2024; 30:132-145. [PMID: 37756666 DOI: 10.1093/ibd/izad205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Indexed: 09/29/2023]
Abstract
Crohn's disease (CD) is one of the 2 main phenotypes of inflammatory bowel diseases (IBDs); CD ischaracterized by a discontinuous, spontaneously recurring, transmural immunopathology that largely affects the terminal ileum. Crohn's disease exhibits both a relapsing and progressive course, and its prevalence is on the rise globally, mirroring the trends of industrialization. While the precise pathogenesis of CD remains unknown, various factors including immune cell dysregulation, microbial dysbiosis, genetic susceptibility, and environmental factors have been implicated in disease etiology. Animal models, particularly ileitis mouse models, have provided valuable tools for studying the specific mechanisms underlying CD, allowing longitudinal assessment and sampling in interventional preclinical studies. Furthermore, animal models assess to evaluate the distinct role that bacterial and dietary antigens play in causing inflammation, using germ-free animals, involving the introduction of individual bacteria (monoassociation studies), and experimenting with well-defined dietary components. An ideal animal model for studying IBD, specifically CD, should exhibit an inherent intestinal condition that arises spontaneously and closely mimics the distinct transmural inflammation observed in the human disease, particularly in the terminal ileum. We have recently characterized the impact of disease-relevant, noninfectious microbiota and specific bacteria in a mouse model that replicates CD-like ileitis, capturing the intricate nature of human CD, namely the TNF∆ARE mouse model. Using germ-free mice, we studied the impact of different diets on the expansion of disease-relevant pathobionts and on the severity of inflammation. In this review article, we review some of the currently available ileitis mouse models and discuss in detail the TNF∆ARE model of CD-like Ileitis.
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Affiliation(s)
- Amira Metwaly
- Chair of Nutrition and Immunology, Technical University of Munich, Freising, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technical University of Munich, Freising, Germany
- ZIEL Institute for Food and Health, Technical University of Munich, Freising, Germany
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14
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Bhat MA, Usman I, Dhaneshwar S. Application of Drug Repurposing Approach for Therapeutic Intervention of Inflammatory Bowel Disease. Curr Rev Clin Exp Pharmacol 2024; 19:234-249. [PMID: 37859409 DOI: 10.2174/0127724328245156231008154045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 07/07/2023] [Accepted: 08/30/2023] [Indexed: 10/21/2023]
Abstract
Inflammatory bowel disease (IBD), represented by Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract (GIT) characterized by chronic relapsing intestinal inflammation, abdominal pain, cramping, loss of appetite, fatigue, diarrhoea, and weight loss. Although the etiology of IBD remains unclear, it is believed to be an interaction between genes, and environmental factors, such as an imbalance of the intestinal microbiota, changing food habits, an ultra-hygiene environment, and an inappropriate immune system. The development of novel effective therapies is stymied by a lack of understanding of the aetiology of IBD. The current therapy involves the use of aminosalicylates, immunosuppressants, and corticosteroids that can effectively manage symptoms, induce and sustain remission, prevent complications, modify the course of the disease, provide diverse treatment options, showcase advancements in biologic therapies, and enhance the overall quality of life. However, the efficacy of current therapy is overshadowed by a plethora of adverse effects, such as loss of weight, mood swings, skin issues, loss of bone density, higher vulnerability to infections, and elevated blood pressure. Biologicals, like anti-tumour necrosis factor agents, can stimulate an autoimmune response in certain individuals that may diminish the effectiveness of the medication over time, necessitating a switch to alternative treatments. The response of IBD patients to current drug therapy is quite varied, which can lead to disease flares that underlines the urgent need to explore alternative treatment option to address the unmet need of developing new treatment strategies for IBD with high efficacy and fewer adverse effects. Drug repurposing is a novel strategy where existing drugs that have already been validated safe in patients for the management of certain diseases are redeployed to treat other, unindicated diseases. The present narrative review focuses on potential drug candidates that could be repurposed for the management of IBD using on-target and off-target strategies. It covers their preclinical, clinical assessment, mechanism of action, and safety profiles, and forecasts their appropriateness in the management of IBD. The review presents useful insights into the most promising candidates for repurposing, like anti-inflammatory and anti-apoptotic troxerutin, which has been found to improve the DSS-induced colitis in rats, an antiosteoarthritic drug diacetylrhein that has been found to have remarkable ameliorating effects on DSS-induced colitis via anti-oxidant and anti- inflammatory properties and by influencing both apoptosis and pyroptosis. Topiramate, an antiepileptic and anticonvulsant drug, has remarkably decreased overall pathophysiological and histopathological events in the experimental model of IBD in rodents by its cytokine inhibitory action.
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Affiliation(s)
- Mohammad Aadil Bhat
- Department of Pharmacology, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, UP, Noida, India
| | - Iqra Usman
- Department of Pharmacology, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, UP, Noida, India
| | - Suneela Dhaneshwar
- Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Amity University Maharashtra, Mumbai, Maharashtra, India
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15
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Moniruzzaman M, Rahman MA, Wang R, Wong KY, Chen ACH, Mueller A, Taylor S, Harding A, Illankoon T, Wiid P, Sajiir H, Schreiber V, Burr LD, McGuckin MA, Phipps S, Hasnain SZ. Interleukin-22 suppresses major histocompatibility complex II in mucosal epithelial cells. J Exp Med 2023; 220:e20230106. [PMID: 37695525 PMCID: PMC10494524 DOI: 10.1084/jem.20230106] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 05/22/2023] [Accepted: 08/18/2023] [Indexed: 09/12/2023] Open
Abstract
Major histocompatibility complex (MHC) II is dynamically expressed on mucosal epithelial cells and is induced in response to inflammation and parasitic infections, upon exposure to microbiota, and is increased in chronic inflammatory diseases. However, the regulation of epithelial cell-specific MHC II during homeostasis is yet to be explored. We discovered a novel role for IL-22 in suppressing epithelial cell MHC II partially via the regulation of endoplasmic reticulum (ER) stress, using animals lacking the interleukin-22-receptor (IL-22RA1), primary human and murine intestinal and respiratory organoids, and murine models of respiratory virus infection or with intestinal epithelial cell defects. IL-22 directly downregulated interferon-γ-induced MHC II on primary epithelial cells by modulating the expression of MHC II antigen A α (H2-Aα) and Class II transactivator (Ciita), a master regulator of MHC II gene expression. IL-22RA1-knockouts have significantly higher MHC II expression on mucosal epithelial cells. Thus, while IL-22-based therapeutics improve pathology in chronic disease, their use may increase susceptibility to viral infections.
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Affiliation(s)
- Md Moniruzzaman
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - M. Arifur Rahman
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Ran Wang
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Kuan Yau Wong
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Alice C.-H. Chen
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Alexandra Mueller
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Steven Taylor
- South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Alexa Harding
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Thishan Illankoon
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Percival Wiid
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Haressh Sajiir
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Veronika Schreiber
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Lucy D. Burr
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
- Department of Respiratory and Sleep Medicine, Mater Health, South Brisbane, Australia
| | - Michael A. McGuckin
- Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia
| | - Simon Phipps
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia
- Respiratory Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Sumaira Z. Hasnain
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia
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16
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Cavalli CAM, Gabbiadini R, Dal Buono A, Quadarella A, De Marco A, Repici A, Bezzio C, Simonetta E, Aliberti S, Armuzzi A. Lung Involvement in Inflammatory Bowel Diseases: Shared Pathways and Unwanted Connections. J Clin Med 2023; 12:6419. [PMID: 37835065 PMCID: PMC10573999 DOI: 10.3390/jcm12196419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/01/2023] [Accepted: 10/06/2023] [Indexed: 10/15/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic, relapsing inflammatory disorders of the gastrointestinal tract, frequently associated with extraintestinal manifestations (EIMs) that can severely affect IBD patients' quality of life, sometimes even becoming life-threatening. Respiratory diseases have always been considered a rare and subsequently neglected extraintestinal manifestations of IBD. However, increasing evidence has demonstrated that respiratory involvement is frequent in IBD patients, even in the absence of respiratory symptoms. Airway inflammation is the most common milieu of IBD-related involvement, with bronchiectasis being the most common manifestation. Furthermore, significant differences in prevalence and types of involvement are present between Crohn's disease and ulcerative colitis. The same embryological origin of respiratory and gastrointestinal tissue, in addition to exposure to common antigens and cytokine networks, may all play a potential role in the respiratory involvement. Furthermore, other causes such as drug-related toxicity and infections must always be considered. This article aims at reviewing the current evidence on the association between IBD and respiratory diseases. The purpose is to raise awareness of respiratory manifestation among IBD specialists and emphasize the need for identifying respiratory diseases in early stages to promptly treat these conditions, avoid worsening morbidity, and prevent lung damage.
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Affiliation(s)
- Carolina Aliai Micol Cavalli
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (C.A.M.C.); (R.G.); (A.D.B.); (A.Q.); (A.D.M.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy; (A.R.); (S.A.)
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (C.A.M.C.); (R.G.); (A.D.B.); (A.Q.); (A.D.M.); (C.B.)
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (C.A.M.C.); (R.G.); (A.D.B.); (A.Q.); (A.D.M.); (C.B.)
| | - Alessandro Quadarella
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (C.A.M.C.); (R.G.); (A.D.B.); (A.Q.); (A.D.M.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy; (A.R.); (S.A.)
| | - Alessandro De Marco
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (C.A.M.C.); (R.G.); (A.D.B.); (A.Q.); (A.D.M.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy; (A.R.); (S.A.)
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy; (A.R.); (S.A.)
- Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Cristina Bezzio
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (C.A.M.C.); (R.G.); (A.D.B.); (A.Q.); (A.D.M.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy; (A.R.); (S.A.)
| | - Edoardo Simonetta
- Respiratory Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Stefano Aliberti
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy; (A.R.); (S.A.)
- Respiratory Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (C.A.M.C.); (R.G.); (A.D.B.); (A.Q.); (A.D.M.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy; (A.R.); (S.A.)
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17
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Gordon H, Rodger B, Lindsay JO, Stagg AJ. Recruitment and Residence of Intestinal T Cells - Lessons for Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1326-1341. [PMID: 36806613 DOI: 10.1093/ecco-jcc/jjad027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Indexed: 02/23/2023]
Abstract
Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.
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Affiliation(s)
- Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Beverley Rodger
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
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18
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Scalia F, Carini F, David S, Giammanco M, Mazzola M, Rappa F, Bressan NI, Maida G, Tomasello G. Inflammatory Bowel Diseases: An Updated Overview on the Heat Shock Protein Involvement. Int J Mol Sci 2023; 24:12129. [PMID: 37569505 PMCID: PMC10419025 DOI: 10.3390/ijms241512129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) represent chronic idiopathic disorders, including Crohn's disease (CD) and ulcerative colitis (UC), in which one of the trigger factors is represented by aberrant immune interactions between the intestinal epithelium and the intestinal microbiota. The involvement of heat shock proteins (HSPs) as etiological and pathogenetic factors is becoming of increasing interest. HSPs were found to be differentially expressed in the intestinal tissues and sera of patients with CD and UC. It has been shown that HSPs can play a dual role in the disease, depending on the stage of progression. They can support the inflammatory and fibrosis process, but they can also act as protective factors during disease progression or before the onset of one of the worst complications of IBD, colorectal cancer. Furthermore, HSPs are able to mediate the interaction between the intestinal microbiota and intestinal epithelial cells. In this work, we discuss the involvement of HSPs in IBD considering their genetic, epigenetic, immune and molecular roles, referring to the most recent works present in the literature. With our review, we want to shed light on the importance of further exploring the role of HSPs, or even better, the role of the molecular chaperone system (CS), in IBD: various molecules of the CS including HSPs may have diagnostic, prognostic and therapeutic potential, promoting the creation of new drugs that could overcome the side-effects of the therapies currently used.
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Affiliation(s)
- Federica Scalia
- Biomedicine, Neurosciences and Advanced Diagnostics BIND, School of Medicine, University of Palermo, 90133 Palermo, Italy; (F.C.); (M.M.); (F.R.); (G.M.); (G.T.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Francesco Carini
- Biomedicine, Neurosciences and Advanced Diagnostics BIND, School of Medicine, University of Palermo, 90133 Palermo, Italy; (F.C.); (M.M.); (F.R.); (G.M.); (G.T.)
- Hospital University School of Medicine, P. Giaccone, 90127 Palermo, Italy
| | - Sabrina David
- Department Surgical, Oncological and Oral Sciences, School of Medicine, University of Palermo, 90133 Palermo, Italy; (S.D.); (M.G.)
| | - Marco Giammanco
- Department Surgical, Oncological and Oral Sciences, School of Medicine, University of Palermo, 90133 Palermo, Italy; (S.D.); (M.G.)
| | - Margherita Mazzola
- Biomedicine, Neurosciences and Advanced Diagnostics BIND, School of Medicine, University of Palermo, 90133 Palermo, Italy; (F.C.); (M.M.); (F.R.); (G.M.); (G.T.)
| | - Francesca Rappa
- Biomedicine, Neurosciences and Advanced Diagnostics BIND, School of Medicine, University of Palermo, 90133 Palermo, Italy; (F.C.); (M.M.); (F.R.); (G.M.); (G.T.)
- Institute of Translational Pharmacology (IFT), Section of Palermo, Italy National Research Council of Italy (CNR), 90146 Palermo, Italy
| | | | - Giorgio Maida
- Biomedicine, Neurosciences and Advanced Diagnostics BIND, School of Medicine, University of Palermo, 90133 Palermo, Italy; (F.C.); (M.M.); (F.R.); (G.M.); (G.T.)
| | - Giovanni Tomasello
- Biomedicine, Neurosciences and Advanced Diagnostics BIND, School of Medicine, University of Palermo, 90133 Palermo, Italy; (F.C.); (M.M.); (F.R.); (G.M.); (G.T.)
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Andersen V, Bennike TB, Bang C, Rioux JD, Hébert-Milette I, Sato T, Hansen AK, Nielsen OH. Investigating the Crime Scene-Molecular Signatures in Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:11217. [PMID: 37446397 PMCID: PMC10342864 DOI: 10.3390/ijms241311217] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and progression. Understanding the link between these factors is crucial for identifying molecular signatures that identify biomarkers to advance the management of IBD. Recent technological breakthroughs and data integration have fuelled the intensity of this research. This research demonstrates that the effect of diet depends on patient factors and gut microbial activity. It also identifies a range of potential biomarkers for IBD management, including mucosa-derived cytokines, gasdermins and neutrophil extracellular traps, all of which need further evaluation before clinical translation. This review provides an update on cutting-edge research in IBD that aims to improve disease management and patient quality of life.
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Affiliation(s)
- Vibeke Andersen
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, Institute of Regional Research, University of Southern Denmark, 5000 Odense, Denmark;
- Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
| | - Tue B. Bennike
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, Institute of Regional Research, University of Southern Denmark, 5000 Odense, Denmark;
- Medical Microbiology and Immunology, Department of Health Science and Technology, Aalborg University, 9000 Aalborg, Denmark
| | - Corinna Bang
- Institute for Clinical Molecular Biology, Christian-Albrecht’s University, 24105 Kiel, Germany;
| | - John D. Rioux
- Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; (J.D.R.); (I.H.-M.)
- Montreal Heart Institute Research Institute, Montreal, QC H1T 1C8, Canada
| | - Isabelle Hébert-Milette
- Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; (J.D.R.); (I.H.-M.)
- Montreal Heart Institute Research Institute, Montreal, QC H1T 1C8, Canada
| | - Toshiro Sato
- Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan;
| | - Axel K. Hansen
- Experimental Animal Models, Department of Veterinary and Animal Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark;
| | - Ole H. Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark
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20
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Alula KM, Theiss AL. Autophagy in Crohn's Disease: Converging on Dysfunctional Innate Immunity. Cells 2023; 12:1779. [PMID: 37443813 PMCID: PMC10341259 DOI: 10.3390/cells12131779] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease marked by relapsing, transmural intestinal inflammation driven by innate and adaptive immune responses. Autophagy is a multi-step process that plays a critical role in maintaining cellular homeostasis by degrading intracellular components, such as damaged organelles and invading bacteria. Dysregulation of autophagy in CD is revealed by the identification of several susceptibility genes, including ATG16L1, IRGM, NOD2, LRRK2, ULK1, ATG4, and TCF4, that are involved in autophagy. In this review, the role of altered autophagy in the mucosal innate immune response in the context of CD is discussed, with a specific focus on dendritic cells, macrophages, Paneth cells, and goblet cells. Selective autophagy, such as xenophagy, ERphagy, and mitophagy, that play crucial roles in maintaining intestinal homeostasis in these innate immune cells, are discussed. As our understanding of autophagy in CD pathogenesis evolves, the development of autophagy-targeted therapeutics may benefit subsets of patients harboring impaired autophagy.
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Affiliation(s)
| | - Arianne L. Theiss
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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21
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Chen X, Zhang H, Zhou X, Wang Y, Shi W. Autotaxin promotes the degradation of the mucus layer by inhibiting autophagy in mouse colitis. Mol Immunol 2023; 160:44-54. [PMID: 37356325 DOI: 10.1016/j.molimm.2023.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 05/06/2023] [Accepted: 06/06/2023] [Indexed: 06/27/2023]
Abstract
Autotaxin (ATX or ENPP2) is an autocrine enzyme associated with the metabolism of various phospholipids. ATX has recently been identified as a regulatory factor in immune-related and inflammation-associated diseases, such as inflammatory bowel disease, but the exact mechanism is unclear. Here, we treated mice with recombinant ATX protein or an ATX inhibitor to investigate the effect of ATX on colitis in mice and the underlying mechanism. In a mouse model of colitis, ATX expression was increased, autophagy was impaired, and the mucus barrier was disrupted. Recombinant ATX protein promoted intestinal inflammation, inhibited autophagy, and disrupted the mucus barrier, while an ATX inhibitor had the opposite effect. Next, we treated mice that received ATX with an autophagy activator and an adenosine 5'-monophosphate-activated protein kinase (AMPK) agonist. We observed that autophagy activator and AMPK agonist could repair the mucus barrier and alleviate intestinal inflammation in ATX-treated mice. In vitro, we obtained consistent results. Thus, we concluded that ATX could inhibit autophagy through the AMPK pathway, which consequently disordered the mucus barrier and aggravated intestinal inflammation.
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Affiliation(s)
- Xiaoyan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China; The State Key Laboratory of Digestive Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hui Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaojiang Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yunwu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wenjie Shi
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
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22
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Chauvin C, Alvarez-Simon D, Radulovic K, Boulard O, Laine W, Delacre M, Waldschmitt N, Segura E, Kluza J, Chamaillard M, Poulin LF. NOD2 in monocytes negatively regulates macrophage development through TNFalpha. Front Immunol 2023; 14:1181823. [PMID: 37415975 PMCID: PMC10320732 DOI: 10.3389/fimmu.2023.1181823] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/23/2023] [Indexed: 07/08/2023] Open
Abstract
Objective It is believed that intestinal recruitment of monocytes from Crohn's Disease (CD) patients who carry NOD2 risk alleles may repeatedly give rise to recruitment of pathogenic macrophages. We investigated an alternative possibility that NOD2 may rather inhibit their differentiation from intravasating monocytes. Design The monocyte fate decision was examined by using germ-free mice, mixed bone marrow chimeras and a culture system yielding macrophages and monocyte-derived dendritic cells (mo-DCs). Results We observed a decrease in the frequency of mo-DCs in the colon of Nod2-deficient mice, despite a similar abundance of monocytes. This decrease was independent of the changes in the gut microbiota and dysbiosis caused by Nod2 deficiency. Similarly, the pool of mo-DCs was poorly reconstituted in a Nod2-deficient mixed bone marrow (BM) chimera. The use of pharmacological inhibitors revealed that activation of NOD2 during monocyte-derived cell development, dominantly inhibits mTOR-mediated macrophage differentiation in a TNFα-dependent manner. These observations were supported by the identification of a TNFα-dependent response to muramyl dipeptide (MDP) that is specifically lost when CD14-expressing blood cells bear a frameshift mutation in NOD2. Conclusion NOD2 negatively regulates a macrophage developmental program through a feed-forward loop that could be exploited for overcoming resistance to anti-TNF therapy in CD.
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Affiliation(s)
- Camille Chauvin
- U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France
- INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
| | - Daniel Alvarez-Simon
- U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France
| | - Katarina Radulovic
- Unité de Recherche Clinique, Centre Hospitalier de Valenciennes, Valenciennes CEDEX, France
| | | | - William Laine
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, Lille, France
| | - Myriam Delacre
- U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France
| | - Nadine Waldschmitt
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Elodie Segura
- INSERM U932, Institut Curie, Paris Sciences et Lettres Research University, Paris, France
| | - Jérome Kluza
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, Lille, France
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23
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Abstract
Mycobacteria are responsible for several human and animal diseases. NOD2 is a pattern recognition receptor that has an important role in mycobacterial recognition. However, the mechanisms by which mutations in NOD2 alter the course of mycobacterial infection remain unclear. Herein, we aimed to review the totality of studies directly addressing the relationship between NOD2 and mycobacteria as a foundation for moving the field forward. NOD2 was linked to mycobacterial infection at 3 levels: (1) genetic, through association with mycobacterial diseases of humans; (2) chemical, through the distinct NOD2 ligand in the mycobacterial cell wall; and (3) immunologic, through heightened NOD2 signaling caused by the unique modification of the NOD2 ligand. The immune response to mycobacteria is shaped by NOD2 signaling, responsible for NF-κB and MAPK activation, and the production of various immune effectors like cytokines and nitric oxide, with some evidence linking this to bacteriologic control. Absence of NOD2 during mycobacterial infection of mice can be detrimental, but the mechanism remains unknown. Conversely, the success of immunization with mycobacteria has been linked to NOD2 signaling and NOD2 has been targeted as an avenue of immunotherapy for diseases even beyond mycobacteria. The mycobacteria-NOD2 interaction remains an important area of study, which may shed light on immune mechanisms in disease.
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Affiliation(s)
- Jean-Yves Dubé
- Department of Microbiology and Immunology, McGill University, Montréal, Canada
| | - Marcel A. Behr
- Department of Medicine, McGill University Health Centre, Montréal, Canada
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24
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Alfaifi J, Germain A, Heba AC, Arnone D, Gailly L, Ndiaye NC, Viennois E, Caron B, Peyrin-Biroulet L, Dreumont N. Deep Dive Into MicroRNAs in Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:986-999. [PMID: 36545755 DOI: 10.1093/ibd/izac250] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Indexed: 06/02/2023]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is thought to develop in genetically predisposed individuals as a consequence of complex interactions between dysregulated inflammatory stimuli, immunological responses, and environmental factors. The pathogenesis of IBD has yet to be fully understood. The global increase in the incidence of IBD suggests a gap in the current understanding of the disease. The development of a new diagnostic tool for inflammatory bowel disease that is both less invasive and more cost-effective would allow for better management of this condition. MicroRNAs (miRNAs) are a class of noncoding RNAs with important roles as posttranscriptional regulators of gene expression, which has led to new insights into understanding IBD. Using techniques such as microarrays and real-time polymerase chain reactions, researchers have investigated the patterns in which patients with Crohn's disease and ulcerative colitis show alterations in the expression of miRNA in tissue, blood, and feces. These miRNAs are found to be differentially expressed in IBD and implicated in its pathogenesis through alterations in autophagy, intestinal barrier, and immune homeostasis. In this review, we discuss the miRNA expression profiles associated with IBD in tissue, peripheral blood, and feces and provide an overview of the miRNA mechanisms involved in IBD.
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Affiliation(s)
- Jaber Alfaifi
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Adeline Germain
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Anne-Charlotte Heba
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Djésia Arnone
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Laura Gailly
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Ndeye Coumba Ndiaye
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Emilie Viennois
- INSERM U1149, Center of Research on Inflammation, Université de Paris, Paris, France
| | - Bénédicte Caron
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Laurent Peyrin-Biroulet
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Natacha Dreumont
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
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25
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Mu C, Zhao Q, Zhao Q, Yang L, Pang X, Liu T, Li X, Wang B, Fung SY, Cao H. Multi-omics in Crohn's disease: New insights from inside. Comput Struct Biotechnol J 2023; 21:3054-3072. [PMID: 37273853 PMCID: PMC10238466 DOI: 10.1016/j.csbj.2023.05.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 06/06/2023] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) with complex clinical manifestations such as chronic diarrhea, weight loss and hematochezia. Despite the increasing incidence worldwide, cure of CD remains extremely difficult. The rapid development of high-throughput sequencing technology with integrated-omics analyses in recent years has provided a new means for exploring the pathogenesis, mining the biomarkers and designing targeted personalized therapeutics of CD. Host genomics and epigenomics unveil heredity-related mechanisms of susceptible individuals, while microbiome and metabolomics map host-microbe interactions in CD patients. Proteomics shows great potential in searching for promising biomarkers. Nonetheless, single omics technology cannot holistically connect the mechanisms with heterogeneity of pathological behavior in CD. The rise of multi-omics analysis integrates genetic/epigenetic profiles with protein/microbial metabolite functionality, providing new hope for comprehensive and in-depth exploration of CD. Herein, we emphasized the different omics features and applications of CD and discussed the current research and limitations of multi-omics in CD. This review will update and deepen our understanding of CD from integration of broad omics spectra and will provide new evidence for targeted individualized therapeutics.
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Affiliation(s)
- Chenlu Mu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qianjing Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qing Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Lijiao Yang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xiaoqi Pang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xiaomeng Li
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Shan-Yu Fung
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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26
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Kasprzak A. Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia. Int J Mol Sci 2023; 24:ijms24043665. [PMID: 36835075 PMCID: PMC9959216 DOI: 10.3390/ijms24043665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Along with apoptosis and inflammation, autophagy is one of three important mechanisms in CRC. The presence of autophagy/mitophagy in most normal mature intestinal epithelial cells has been confirmed, where it has mainly protective functions against reactive oxygen species (ROS)-induced DNA and protein damage. Autophagy regulates cell proliferation, metabolism, differentiation, secretion of mucins and/or anti-microbial peptides. Abnormal autophagy in intestinal epithelial cells leads to dysbiosis, a decline in local immunity and a decrease in cell secretory function. The insulin-like growth factor (IGF) signaling pathway plays an important role in colorectal carcinogenesis. This is evidenced by the biological activities of IGFs (IGF-1 and IGF-2), IGF-1 receptor type 1 (IGF-1R) and IGF-binding proteins (IGF BPs), which have been reported to regulate cell survival, proliferation, differentiation and apoptosis. Defects in autophagy are found in patients with metabolic syndrome (MetS), inflammatory bowel diseases (IBD) and CRC. In neoplastic cells, the IGF system modulates the autophagy process bidirectionally. In the current era of improving CRC therapies, it seems important to investigate the exact mechanisms not only of apoptosis, but also of autophagy in different populations of tumor microenvironment (TME) cells. The role of the IGF system in autophagy in normal as well as transformed colorectal cells still seems poorly understood. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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27
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Wang J, Zhao D, Lei Z, Ge P, Lu Z, Chai Q, Zhang Y, Qiang L, Yu Y, Zhang X, Li B, Zhu S, Zhang L, Liu CH. TRIM27 maintains gut homeostasis by promoting intestinal stem cell self-renewal. Cell Mol Immunol 2023; 20:158-174. [PMID: 36596873 PMCID: PMC9887071 DOI: 10.1038/s41423-022-00963-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/20/2022] [Indexed: 01/05/2023] Open
Abstract
Dysregulation of gut homeostasis is associated with irritable bowel syndrome (IBS), a chronic functional gastrointestinal disorder affecting approximately 11.2% of the global population. The poorly understood pathogenesis of IBS has impeded its treatment. Here, we report that the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) is weakly expressed in IBS but highly expressed in inflammatory bowel disease (IBD), a frequent chronic organic gastrointestinal disorder. Accordingly, knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms, including increased visceral hyperalgesia and abnormal stool features, as observed in IBS patients. Mechanistically, TRIM27 stabilizes β-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell (ISC) self-renewal. Consistent with these findings, Trim27 deficiency disrupts organoid formation, which is rescued by reintroducing TRIM27 or β-catenin. Furthermore, Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal. Taken together, these data indicate that TRIM27 is critical for maintaining gut homeostasis, suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS. Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.
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Affiliation(s)
- Jing Wang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Dongdong Zhao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Zehui Lei
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Pupu Ge
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zhe Lu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Qiyao Chai
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yong Zhang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 100850, China
| | - Lihua Qiang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Yang Yu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Xinwen Zhang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Bingxi Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Shu Zhu
- Institute of Immunology, Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 100850, China.
| | - Cui Hua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China.
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28
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Ribeiro BE, Breves J, de Souza HSP. Pathogenesis: Crohn’s disease and ulcerative colitis. NATURAL PLANT PRODUCTS IN INFLAMMATORY BOWEL DISEASES 2023:9-46. [DOI: 10.1016/b978-0-323-99111-7.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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29
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You Y, Xiao Y, Lu Y, Du J, Cai H, Cai W, Yan W. Postbiotic muramyl dipeptide alleviates colitis via activating autophagy in intestinal epithelial cells. Front Pharmacol 2022; 13:1052644. [PMID: 36506547 PMCID: PMC9727138 DOI: 10.3389/fphar.2022.1052644] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
The pathogenesis of IBD is complicated and still unclear. Nucleotide-binding oligomerization domain 2 (NOD2) plays a significant role in regulating gut inflammation under the activation of muramyl dipeptide (MDP), which is used as a postbiotic. The study aimed to investigate the effect of MDP on the intestinal barrier in colitis and the mechanism involved. In this study, C57BL/6 mice were challenged with dextran sodium sulfate (DSS) for establishing a colitis model with the pre-treatment of MDP in vivo. Intestinal permeability was reflected by detecting the serum concentration of 4 kDa Fluorescein Isothiocyanate-Dextran. The expression of inflammation, barrier-related proteins, and autophagy was tested by Western Blotting. Proliferation and apoptosis in intestinal epithelial cells were detected by immunohistochemistry. Caco-2 cells were exposed to lipopolysaccharide for imitating inflammation in vitro. The findings showed that administration of MDP ameliorated losses of body weight loss, gross injury, and histology score of the colon in the DSS-induced colitis mice. MDP significantly ameliorated the condition of gut permeability, and promoted intestinal barrier repair by increasing the expression of Zonula occludens-1 and E-cadherin. Meanwhile, MDP promoted proliferation and reduced apoptosis of intestinal epithelial cells. In the experiment group treated with MDP, LC3 was upregulated, and p62 was downregulated, respectively. These results suggested that MDP stimulation attenuates intestinal inflammation both in vivo and in vitro. Potentially, MDP reduced the intestinal barrier damage by regulating autophagy in intestinal epithelial cells. Future trials investigating the effects of MDP-based postbiotics on IBD may be promising.
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Affiliation(s)
- Yaying You
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Yongtao Xiao
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Lu
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jun Du
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Hui Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,*Correspondence: Weihui Yan, ; Wei Cai,
| | - Weihui Yan
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,*Correspondence: Weihui Yan, ; Wei Cai,
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30
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Guo XR, He CW, Gao H, Hua RX, Liang C, Du YX, Shang HW, Lu X, Xu JD. Insight into role of short chain fatty acids in regulating intestinal mucosal barrier and alleviating inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2022; 30:928-940. [DOI: 10.11569/wcjd.v30.i21.928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
In recent years, the importance of intestinal microbiota and its metabolites in maintaining the human intestinal environment has been gradually revealed. Therefore, short chain fatty acids (SCFAs), as the metabolites produced by the intestinal microbiota, play a momentous part in regulating the balance between the function and morphology of the mucosal barrier, regulating the proliferation and differentiation of mucosal cells, protecting the integrity and permeability of the mucosal barrier, and maintainingthe stability of tight junctions. Inflammatory bowel disease (IBD) is a chronic, inflammatory condition of the gastrointestinal tract, associated with a disturbance of intestinal barrier function and dysregulation of the intestinal immune responses, the etiology and pathogenesis of which, however, are not yet fully uncovered. Animal models and human studies have corroborated the contribution of SCFAs in enhancing the barrier function through protective effects. This review will summarize the potential role of SCFAs in IBD with regard to regulating intestinal function, hoping to provide a new target for clinical treatment of IBD.
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Affiliation(s)
- Xue-Ran Guo
- 2019 Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Cheng-Wei He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Han Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Rong-Xuan Hua
- 2020 Clinical Medicine of "5+3" Program, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Chen Liang
- 2019 Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Yi-Xuan Du
- 2020 Oral Medicine of "5+3" Program, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Hong-Wei Shang
- Teaching Laboratory of Morphology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Xin Lu
- Teaching Laboratory of Morphology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
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31
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Cosme D, Soares-da-Silva P, Magro F. Effect of Toll-like receptor-2, -4, -5, -7, and NOD2 stimulation on potassium channel conductance in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2022; 323:G410-G419. [PMID: 36040119 DOI: 10.1152/ajpgi.00139.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Disproportionate activation of pattern recognition receptors plays a role in inflammatory bowel disease (IBD) pathophysiology. Diarrhea is a hallmark symptom of IBD, resulting at least in part from an electrolyte imbalance that may be caused by changes in potassium channel activity. We evaluated the impact of Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain 2 (NOD2) stimulation on potassium conductance of the basolateral membrane in human intestinal epithelial cells (IECs) and the role of potassium channels through electrophysiological assays under short-circuit current in Ussing chambers. TLRs and NOD2 were stimulated using specific agonists, and potassium channels were selectively blocked using triarylmethane-34 (TRAM-34), adenylyl-imidodiphosphate (AMP-PNP), and BaCl2. Potassium conductance of the basolateral membrane decreased upon activation of TLR2, TLR4, and TLR7 in T84 cells (means ± SE, -11.2 ± 4.5, -40.4 ± 7.2, and -19.4 ± 5.9, respectively) and in Caco-2 cells (-13.1 ± 5.7, -55.7 ± 7.4, and -29.1 ± 7.2, respectively). In contrast, activation of TLR5 and NOD2 increased basolateral potassium conductance, both in T84 cells (18.0 ± 4.1 and 18.4 ± 2.8, respectively) and in Caco-2 cells (21.2 ± 8.4 and 16.0 ± 3.6, respectively). TRAM-34 and AMP-PNP induced a decrease in basolateral potassium conductance upon TLR4 stimulation in both cell lines. Both KCa3.1- and Kir6-channels appear to be important mediators of this effect in IECs and could be potential targets for therapeutic agent development.NEW & NOTEWORTHY This study highlights that PRRs stimulation directly influences K+-channel conductance in IECs. TLR-2, -4, -7 stimulation decreased K+ conductance, whereas TLR5 and NOD2 stimulation had the opposite effect, leading to an increase of it instead. This study reports for the first time that KCa3.1- and Kir6-channels play a role in K+ transport pathways triggered by TLR4 stimulation. These findings suggest that KCa3.1- and Kir6-channels modulation may be a potential target for new therapeutic agents in IBD.
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Affiliation(s)
- Dina Cosme
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,MedInUP, Center for Drug Discovery and Innovative Medicines, Porto, Portugal
| | - Patrício Soares-da-Silva
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,MedInUP, Center for Drug Discovery and Innovative Medicines, Porto, Portugal
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Gastroenterology, São João Hospital University Centre, Porto, Portugal.,Center for Health Technology and Services Research, Porto, Portugal.,Clinical Pharmacology Unit, São João Hospital University Centre, Porto, Portugal.,Portuguese Inflammatory Bowel Disease Group, Porto, Portugal
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32
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Yu C, Rao D, Wang T, Song J, Zhang L, Huang W. Emerging roles of TRIM27 in cancer and other human diseases. Front Cell Dev Biol 2022; 10:1004429. [PMID: 36200036 PMCID: PMC9527303 DOI: 10.3389/fcell.2022.1004429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/05/2022] [Indexed: 12/24/2022] Open
Abstract
As a member of the TRIM protein family, TRIM27 is a RING-mediated E3 ubiquitin ligase that can mark other proteins for degradation. Its ubiquitination targets include PTEN, IκBα and p53, which allows it to regulate many signaling pathways to exert its functions under both physiological and pathological conditions, such as cell proliferation, differentiation and apoptosis. During the past decades, TRIM27 was reported to be involved in many diseases, including cancer, lupus nephritis, ischemia-reperfusion injury and Parkinson’s disease. Although the research interest in TRIM27 is increasing, there are few reviews about the diverse roles of this protein. Here, we systematically review the roles of TRIM27 in cancer and other human diseases. Firstly, we introduce the biological functions of TRIM27. Next, we focus on the roles of TRIM27 in cancer, including ovarian cancer, breast cancer and lung cancer. At the same time, we also describe the roles of TRIM27 in other human diseases, such as lupus nephritis, ischemia-reperfusion injury and Parkinson’s disease. Finally, we discuss the future directions of TRIM27 research, especially its potential roles in tumor immunity.
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Affiliation(s)
- Chengpeng Yu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Rao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Tiantian Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jia Song, ; Lei Zhang, ; Wenjie Huang,
| | - Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University, Jinzhong, China
- Tongji Medical College, Shanxi Tongji Hospital, Huazhong University of Science and Technology, Taiyuan, China
- *Correspondence: Jia Song, ; Lei Zhang, ; Wenjie Huang,
| | - Wenjie Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jia Song, ; Lei Zhang, ; Wenjie Huang,
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33
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Schmid F, Chao CM, Däbritz J. Pathophysiological Concepts and Management of Pulmonary Manifestation of Pediatric Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:7287. [PMID: 35806292 PMCID: PMC9266732 DOI: 10.3390/ijms23137287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 06/28/2022] [Accepted: 06/28/2022] [Indexed: 02/01/2023] Open
Abstract
Pulmonary manifestation (PM) of inflammatory bowel disease (IBD) in children is a rare condition. The exact pathogenesis is still unclear, but several explanatory concepts were postulated and several case reports in children were published. We performed a systematic Medline search between April 1976 and April 2022. Different pathophysiological concepts were identified, including the shared embryological origin, "miss-homing" of intestinal based neutrophils and T lymphocytes, inflammatory triggering via certain molecules (tripeptide proline-glycine-proline, interleukin 25), genetic factors and alterations in the microbiome. Most pediatric IBD patients with PM are asymptomatic, but can show alterations in pulmonary function tests and breathing tests. In children, the pulmonary parenchyma is more affected than the airways, leading histologically mainly to organizing pneumonia. Medication-associated lung injury has to be considered in pulmonary symptomatic pediatric IBD patients treated with certain agents (i.e., mesalamine, sulfasalazine or infliximab). Furthermore, the risk of pulmonary embolism is generally increased in pediatric IBD patients. The initial treatment of PM is based on corticosteroids, either inhaled for the larger airways or systemic for smaller airways and parenchymal disease. In summary, this review article summarizes the current knowledge about PM in pediatric IBD patients, focusing on pathophysiological and clinical aspects.
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Affiliation(s)
- Florian Schmid
- Catholic Children’s Hospital Wilhelmstift, 22149 Hamburg, Germany;
| | - Cho-Ming Chao
- Department of Pediatrics, University Medical Center Rostock, 18057 Rostock, Germany;
- Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center of Lung Research (DZL), Justus-Liebig-University, 35398 Giessen, Germany
| | - Jan Däbritz
- Department of Pediatrics, University Medical Center Greifswald, 17475 Greifswald, Germany
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34
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Mommersteeg M, Simovic I, Yu B, van Nieuwenburg S, Bruno IM, Doukas M, Kuipers E, Spaander M, Peppelenbosch M, Castaño-Rodríguez N, Fuhler G. Autophagy mediates ER stress and inflammation in Helicobacter pylori-related gastric cancer. Gut Microbes 2022; 14:2015238. [PMID: 34965181 PMCID: PMC8726742 DOI: 10.1080/19490976.2021.2015238] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Autophagy is a cellular degradation mechanism, which is triggered by the bacterium Helicobacter pylori. A single nucleotide polymorphism (SNP) in the autophagy gene ATG16L1 (rs2241880, G-allele) has been shown to dysregulate autophagy and increase intestinal endoplasmic reticulum (ER) stress. Here, we investigate the role of this SNP in H.pylori-mediated gastric carcinogenesis and its molecular pathways. ATG16L1 rs2241880 was genotyped in subjects from different ethnic cohorts (Dutch and Australian) presenting with gastric (pre)malignant lesions of various severity. Expression of GRP78 (a marker for ER stress) was assessed in gastric tissues. The effect of ATG16L1 rs2241880 on H.pylori-mediated ER stress and pro-inflammatory cytokine induction was investigated in organoids and CRISPR/Cas9 modified cell lines. Development of gastric cancer was associated with the ATG16L1 rs2241880 G-allele. Intestinal metaplastic cells in gastric tissue of patients showed increased levels of ER-stress. In vitro models showed that H.pylori increases autophagy while reducing ER stress, which appeared partly mediated by the ATG16L1 rs2241880 genotype. H.pylori-induced IL-8 production was increased while TNF-α production was decreased, in cells homozygous for the G-allele. The ATG16L1 rs2241880 G-allele is associated with progression of gastric premalignant lesions and cancer. Modulation of H.pylori-induced ER stress pathways and pro-inflammatory mediators by ATG16L1 rs2441880 may underlie this increased risk.
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Affiliation(s)
- M.C. Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - I. Simovic
- School of Biotechnology and Biomolecular Sciences, Unsw, Sydney, Australia
| | - B. Yu
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - S.A.V. van Nieuwenburg
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - I, M.J. Bruno
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M. Doukas
- Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - E.J. Kuipers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M.C.W. Spaander
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M.P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - N. Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, Unsw, Sydney, Australia,CONTACT N. Castaño-Rodríguez School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW 2052, Australia
| | - G.M. Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands,G.M. Fuhler PhD Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Unsw, Rotterdam, The Netherlands
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35
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Harapas CR, Idiiatullina E, Al-Azab M, Hrovat-Schaale K, Reygaerts T, Steiner A, Laohamonthonkul P, Davidson S, Yu CH, Booty L, Masters SL. Organellar homeostasis and innate immune sensing. Nat Rev Immunol 2022; 22:535-549. [PMID: 35197578 DOI: 10.1038/s41577-022-00682-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2022] [Indexed: 02/06/2023]
Abstract
A cell is delimited by numerous borders that define specific organelles. The walls of some organelles are particularly robust, such as in mitochondria or endoplasmic reticulum, but some are more fluid such as in phase-separated stress granules. Either way, all organelles can be damaged at times, leading their contents to leak out into the surrounding environment. Therefore, an elegant way to construct an innate immune defence system is to recognize host molecules that do not normally reside within a particular compartment. Here, we provide several examples where organellar homeostasis is lost, leading to the activation of a specific innate immune sensor; these include NLRP3 activation owing to a disrupted trans-Golgi network, Pyrin activation due to cytoskeletal damage, and cGAS-STING activation following the leakage of nuclear or mitochondrial DNA. Frequently, organelle damage is observed downstream of pathogenic infection but it can also occur in sterile settings as associated with auto-inflammatory disease. Therefore, understanding organellar homeostasis is central to efforts that will identify new innate immune pathways, and therapeutics that balance organellar homeostasis, or target the breakdown pathways that trigger innate immune sensors, could be useful treatments for infection and chronic inflammatory diseases.
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Affiliation(s)
- Cassandra R Harapas
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Elina Idiiatullina
- Immunology Laboratory, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou, Guangdong, China
| | - Mahmoud Al-Azab
- Immunology Laboratory, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou, Guangdong, China
| | - Katja Hrovat-Schaale
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Thomas Reygaerts
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Annemarie Steiner
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.,Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany
| | - Pawat Laohamonthonkul
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Sophia Davidson
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Chien-Hsiung Yu
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Lee Booty
- Immunology Network, Immunology Research Unit, GSK, Stevenage, UK
| | - Seth L Masters
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. .,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. .,Immunology Laboratory, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou, Guangdong, China.
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36
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Furuya Y, Fukai K, Nakazawa S, Kojimahara N, Hoshi K, Toyota A, Tatemichi M. Occupational physical activity differentially affects the risk for developing later-onset Crohn's disease and ulcerative colitis among middle-aged and older populations. Scand J Gastroenterol 2022; 57:206-213. [PMID: 34762552 DOI: 10.1080/00365521.2021.1999495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND A person's occupation may increase his/her risk for developing inflammatory bowel disease (IBD). This study investigated the association between risk for later-onset of IBD and both specific occupations and occupational physical activity (OPA) levels. MATERIALS AND METHODS A multicenter hospital-based matched case-control study was conducted using the Inpatient Clinico-Occupational Survey database. Cases were patients with Crohn's disease (CD) and ulcerative colitis (UC) patients admitted for the first time between 2005 and 2015. Four controls matched by age, sex, admission year and hospital were selected for each case. Cases and controls were grouped into the longest-held occupations as classified by the Japanese Standard Occupational Classification and OPA levels. We conducted conditional logistic regressions to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for IBD, CD and UC adjusted for alcohol consumption and smoking status. RESULTS There were 564 cases (172 CD, 392 UC) and 2086 controls. The risk for UC was higher among sales workers and carrying, cleaning and packing workers (ORs 2.62 [95%CIs 1.18-5.82], 2.52 [1.04-6.09]). There was no association between occupation type and CD risk. Higher OPA level decreased CD risk (OR 0.51 [95%CIs 0.26-1.00]) and increased UC risk (OR 1.53 [95%CIs 1.02-2.30]). CONCLUSIONS Our study revealed that the risk for later-onset of UC, but not CD, was associated with longest-held 'service' and 'manufacture' work. The risk by OPA levels was inversely associated between CD and UC. Further studies are needed by follow-up method for long-term effects of physical activity.
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Affiliation(s)
- Yuko Furuya
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Shoko Nakazawa
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | | | - Keika Hoshi
- Center of Public Health Informatics, National Institute of Public Health, Wako, Japan.,Department of Hygiene, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Akihiro Toyota
- Chugoku Rosai Hospital Research Center for the Promotion of Health and Employment Support, Japan Organization of Occupational Health and Safety, Kure, Japan
| | - Masayuki Tatemichi
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
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Ren Y, Liu W, Zhang J, Bi J, Fan M, Lv Y, Wu Z, Zhang Y, Wu R. MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells. Front Cell Dev Biol 2022; 9:803876. [PMID: 35096831 PMCID: PMC8795834 DOI: 10.3389/fcell.2021.803876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/27/2021] [Indexed: 01/25/2023] Open
Abstract
Excessive endoplasmic reticulum (ER) stress contributes significantly to the pathogenesis of exocrine acinar damage in acute pancreatitis. Our previous study found that milk fat globule EGF factor 8 (MFG-E8), a lipophilic glycoprotein, alleviates acinar cell damage during AP via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining cellular homeostasis. However, MFG-E8's role in ER stress in pancreatic exocrine acinar cells has not been evaluated. To study this, thapsigargin, brefeldin A, tunicamycin and cerulein + LPS were used to induce ER stress in rat pancreatic acinar cells in vitro. L-arginine- and cerulein + LPS-induced acute pancreatitis in mice were used to study ER stress in vivo. The results showed that MFG-E8 dose-dependently inhibited ER stress under both in vitro and in vivo conditions. MFG-E8 knockout mice suffered more severe ER stress and greater inflammatory response after L-arginine administration. Mechanistically, MFG-E8 increased phosphorylation of FAK and STAT3 in cerulein + LPS-treated pancreatic acinar cells. The presence of specific inhibitors of αvβ3/5 integrin, FAK or STAT3 abolished MFG-E8's effect on cerulein + LPS-induced ER stress in pancreatic acinar cells. In conclusion, MFG-E8 maintains cellular homeostasis by alleviating ER stress in pancreatic exocrine acinar cells.
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Affiliation(s)
- Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wuming Liu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Meng Fan
- Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yuanyuan Zhang
- Department of Pediatrics, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,*Correspondence: Yuanyuan Zhang, ; Rongqian Wu,
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,*Correspondence: Yuanyuan Zhang, ; Rongqian Wu,
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38
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Shi H, Sun S, Zhou X, He Y, Peng Q. GBP4 is an immune-related biomarker for patients with ileocolonic Crohn’s disease by comprehensive analysis. EUR J INFLAMM 2022. [DOI: 10.1177/1721727x221116743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: Extensive evidence has shown that immune cell infiltration is associated with the pathogenesis of Crohn’s disease (CD). Methods: Differentially expressed genes (DEGs) from the GSE179285 dataset in the intestinal mucosa of CD patients and healthy individuals were then identified. The infiltration pattern of 22 immune cell types was assessed using the CIBERSORT algorithm. The DEGs and 22 immune cell types were combined to find the key gene network using weighted gene co-expression network analysis (WGCNA). A linear regression model for the relationship between the expression of the hub genes in CD patients and infiltration of immune cells was also developed. The utility and accuracy of the hub genes for CD diagnosis were assessed using receiver operating characteristic (ROC) analysis. The accuracy of the model was validated using the GSE20881 dataset. Results: There were 1135 DEGs between the intestinal mucosal tissue of CD patients and healthy individuals. Of these DEGs, 711 genes were upregulated, whereas 424 of them were downregulated. There was also a significant difference in the infiltration of immune cells to the intestinal mucosal between the CD patients and healthy individuals. WGCNA revealed that the turquoise module genes were strongly correlated with the infiltration of M1 macrophages (cor =0.68, p = 10−16). Finally, the expression of GBP4, the identified hub gene, strongly correlated with the infiltration of M1 macrophages (adjusted r-squared =0.661, p < 2×10−16), and is a relatively good marker for CD diagnostic prediction (AUC =0.736). The relationship between GBP4 expression and infiltration of M1 macrophages (adjusted r-squared =0.435, p < 2×10−16) and diagnostic value of the gene (AUC =0.702) were verified using the GSE20881 validation dataset. Conclusion: The expression of GBP4 is associated with the infiltration of M1 macrophages to the intestinal mucosa of CD patients.
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Affiliation(s)
- Heng Shi
- Department of Gastroenterology, The Central Hospital of Shaoyang, University of South China, Shaoyang, Hunan Province, China
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong Province, China
| | - Shengyun Sun
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong Province, China
| | - Xianling Zhou
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong Province, China
| | - Yushan He
- Department of Gastroenterology, The Central Hospital of Shaoyang, University of South China, Shaoyang, Hunan Province, China
| | - Qin Peng
- Department of Gastroenterology, The Central Hospital of Shaoyang, University of South China, Shaoyang, Hunan Province, China
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Zhang YM. Orosomucoid-like protein 3, rhinovirus and asthma. World J Crit Care Med 2021; 10:170-182. [PMID: 34616654 PMCID: PMC8462028 DOI: 10.5492/wjccm.v10.i5.170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
The genetic variants of orosomucoid-like protein 3 (ORMDL3) gene are associated with highly significant increases in the number of human rhinovirus (HRV)-induced wheezing episodes in children. Recent investigations have been focused on the mechanisms of ORMDL3 in rhinovirus infection for asthma and asthma exacerbations. ORMDL3 not only regulates major human rhinovirus receptor intercellular adhesion molecule 1 expression, but also plays pivotal roles in viral infection through metabolisms of ceramide and sphingosine-1-phosphate, endoplasmic reticulum (ER) stress, ER-Golgi interface and glycolysis. Research on the roles of ORMDL3 in HRV infection will lead us to identify new biomarkers and novel therapeutic targets in childhood asthma and viral induced asthma exacerbations.
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Affiliation(s)
- You-Ming Zhang
- Section of Genomic and Environmental Medicine, National Heart and Lung Institute, Molecular Genetics Group, Division of Respiratory Sciences, Imperial College London, London SW3 6LY, United Kingdom
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40
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Thein W, Po WW, Choi WS, Sohn UD. Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches. Biomol Ther (Seoul) 2021; 29:353-364. [PMID: 34127572 PMCID: PMC8255139 DOI: 10.4062/biomolther.2021.086] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/11/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.
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Affiliation(s)
- Wynn Thein
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Wah Wah Po
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Won Seok Choi
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Uy Dong Sohn
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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41
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Ruiz Castro PA, Yepiskoposyan H, Gubian S, Calvino-Martin F, Kogel U, Renggli K, Peitsch MC, Hoeng J, Talikka M. Systems biology approach highlights mechanistic differences between Crohn's disease and ulcerative colitis. Sci Rep 2021; 11:11519. [PMID: 34075172 PMCID: PMC8169754 DOI: 10.1038/s41598-021-91124-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/21/2021] [Indexed: 12/11/2022] Open
Abstract
The molecular mechanisms of IBD have been the subject of intensive exploration. We, therefore, assembled the available information into a suite of causal biological network models, which offer comprehensive visualization of the processes underlying IBD. Scientific text was curated by using Biological Expression Language (BEL) and compiled with OpenBEL 3.0.0. Network properties were analysed by Cytoscape. Network perturbation amplitudes were computed to score the network models with transcriptomic data from public data repositories. The IBD network model suite consists of three independent models that represent signalling pathways that contribute to IBD. In the “intestinal permeability” model, programmed cell death factors were downregulated in CD and upregulated in UC. In the “inflammation” model, PPARG, IL6, and IFN-associated pathways were prominent regulatory factors in both diseases. In the “wound healing” model, factors promoting wound healing were upregulated in CD and downregulated in UC. Scoring of publicly available transcriptomic datasets onto these network models demonstrated that the IBD models capture the perturbation in each dataset accurately. The IBD network model suite can provide better mechanistic insights of the transcriptional changes in IBD and constitutes a valuable tool in personalized medicine to further understand individual drug responses in IBD.
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Affiliation(s)
- Pedro A Ruiz Castro
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
| | - Hasmik Yepiskoposyan
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
| | - Sylvain Gubian
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland
| | - Florian Calvino-Martin
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland
| | - Ulrike Kogel
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland
| | - Kasper Renggli
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland
| | - Manuel C Peitsch
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland
| | - Julia Hoeng
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland
| | - Marja Talikka
- Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
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Ahmed M, Metwaly A, Haller D. Modeling microbe-host interaction in the pathogenesis of Crohn's disease. Int J Med Microbiol 2021; 311:151489. [PMID: 33676240 DOI: 10.1016/j.ijmm.2021.151489] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 01/19/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Alterations in the gut microbiota structure and function are thought to play an important role in the pathogenesis of Crohn's disease (CD). The rapid advancement of high-throughput sequencing technologies led to the identification of microbiome risk signatures associated with distinct disease phenotypes and progressing disease entities. Functional validation of the identified microbiome signatures is essential to understand the underlying mechanisms of microbe-host interactions. Germfree mouse models are available to study the functional role of disease-conditioning complex gut microbial ecosystems (dysbiosis) or pathobionts (single bacteria) in the pathogenesis of CD-like inflammation. Here, we discuss the clinical and mechanistic relevance and limitations of gnotobiotic mouse models in the context of CD. In addition, we will address the role of diet as an essential external factor modulating microbiome changes, potentially underlying disease initiation and development.
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Affiliation(s)
- Mohamed Ahmed
- Technical University of Munich, Chair of Nutrition and Immunology, School of Life Sciences, 85354 Freising, Germany
| | - Amira Metwaly
- Technical University of Munich, Chair of Nutrition and Immunology, School of Life Sciences, 85354 Freising, Germany
| | - Dirk Haller
- Technical University of Munich, Chair of Nutrition and Immunology, School of Life Sciences, 85354 Freising, Germany; Technical University of Munich, ZIEL Institute for Food & Health, Germany.
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43
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Li Y, Jin R, Li L, Choi JS, Kim J, Yoon HJ, Park JH, Yoon KC. Blue Light Induces Impaired Autophagy through Nucleotide-Binding Oligomerization Domain 2 Activation on the Mouse Ocular Surface. Int J Mol Sci 2021; 22:2015. [PMID: 33670592 PMCID: PMC7922400 DOI: 10.3390/ijms22042015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 02/06/2021] [Indexed: 12/12/2022] Open
Abstract
In this study, we investigated the effects of blue light exposure on nucleotide-binding oligomerization domain 2 (NOD2) expression on the mouse ocular surface and evaluated the role of NOD2 activation in light-induced cell death. Mice were divided into wild-type (WT), NOD2-knock out (KO), WT + blue light (WT + BL), and NOD2-KO + blue light (NOD2-KO + BL) groups, and the mice in the WT+BL and NOD2-KO + BL groups were exposed to blue light for 10 days. After 10 days of blue light exposure, increased reactive oxygen species and malondialdehyde were observed in the WT + BL and NOD2-KO + BL groups, and the WT + BL group showed a higher expression of NOD2 and autophagy related 16 like 1. Although both WT+BL and NOD2-KO + BL groups showed an increase in the expression of light chain 3-II, NOD2-KO + BL mice had a significantly lower p62 expression than WT + BL mice. In addition, NOD2-KO+BL mice had significantly lower corneal epithelial damage and apoptosis than WT + BL mice. In conclusion, blue light exposure can induce impaired autophagy by activation of NOD2 on the ocular surface. In addition, the reactive oxygen species (ROS)-NOD2-autophagy related 16 like 1 (ATG16L) signaling pathway may be involved in the blue-light-induced autophagy responses, resulting in corneal epithelial apoptosis.
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Affiliation(s)
- Ying Li
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Rujun Jin
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Lan Li
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
- Department of Biomedical Sciences and Centers for Creative Biomedical Scientists, Chonnam National University, Gwangju 61469, Korea
| | - Ji Suk Choi
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Jonghwa Kim
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Hyeon Jeong Yoon
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Jong Hwan Park
- Laboratory of Animal Medicine, College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju 77, Korea;
| | - Kyung Chul Yoon
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
- Department of Biomedical Sciences and Centers for Creative Biomedical Scientists, Chonnam National University, Gwangju 61469, Korea
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Zheng W, Chu Q, Xu T. The long noncoding RNA NARL regulates immune responses via microRNA-mediated NOD1 downregulation in teleost fish. J Biol Chem 2021; 296:100414. [PMID: 33581111 PMCID: PMC7966872 DOI: 10.1016/j.jbc.2021.100414] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
Increasing evidence shows that the long noncoding RNA (lncRNA) is a major regulator and participates in the regulation of various physiological and pathological processes, such as cell proliferation, differentiation, metastasis, and apoptosis. Unlike mammals, however, the study of lncRNA in lower invertebrates is just beginning and the extent of lncRNA-mediate regulation remains unclear. Here, we for the first time identify an lncRNA, termed nucleotide oligomerization domain 1 (NOD1) antibacterial and antiviral-related lncRNA (NARL), as a key regulator for innate immunity in teleost fish. We found that NOD1 plays an important role in the antibacterial and antiviral process in fish and that the microRNA miR-217-5p inhibits NOD1 expression and thus weakens the NF-κB and the IRF3-driven signaling pathway. Furthermore, our results indicated that NARL functions as a competing endogenous RNA (ceRNA) for miR-217-5p to regulate protein abundance of NOD1; thus, invading microorganisms are eliminated and immune responses are promoted. Our study also demonstrates the regulation mechanism that lncRNA NARL can competitive adsorption miR-217-5p to regulate the miR-217-5p/NOD1 axis is widespread in teleost fish. Taken together, our results reveal that NARL in fish is a critical positive regulator of innate immune responses to viral and bacterial infection by suppressing a feedback to NOD1-NF-κB/IRF3-mediated signaling.
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Affiliation(s)
- Weiwei Zheng
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qing Chu
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tianjun Xu
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Ministry of Education, Shanghai, China; National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China.
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Li CY, Yang TM, Ou RW, Wei QQ, Shang HF. Genome-wide genetic links between amyotrophic lateral sclerosis and autoimmune diseases. BMC Med 2021; 19:27. [PMID: 33541344 PMCID: PMC7863260 DOI: 10.1186/s12916-021-01903-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 01/05/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture. METHODS To examine the relation between ALS and 10 autoimmune diseases, including asthma, celiac disease (CeD), Crohn's disease (CD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and ulcerative colitis (UC), and identify shared risk loci, we first estimated the genetic correlation using summary statistics from genome-wide association studies, and then analyzed the genetic enrichment leveraging the conditional false discovery rate statistical method. RESULTS We identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD. Robust genetic enrichment was observed between ALS and CeD and MS, and moderate enrichment was found between ALS and UC and T1D. Thirteen shared genetic loci were identified, among which five were suggestively significant in another ALS GWAS, namely rs3828599 (GPX3), rs3849943 (C9orf72), rs7154847 (G2E3), rs6571361 (SCFD1), and rs9903355 (GGNBP2). By integrating cis-expression quantitative trait loci analyses in Braineac and GTEx, we further identified GGNBP2, ATXN3, and SLC9A8 as novel ALS risk genes. Functional enrichment analysis indicated that the shared risk genes were involved in four pathways including membrane trafficking, vesicle-mediated transport, ER to Golgi anterograde transport, and transport to the Golgi and subsequent modification. CONCLUSIONS Our findings demonstrate a specific genetic correlation between ALS and autoimmune diseases and identify shared risk loci, including three novel ALS risk genes. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.
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Affiliation(s)
- Chun Yu Li
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Mi Yang
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China
| | - Ru Wei Ou
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China
| | - Qian Qian Wei
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Fang Shang
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China.
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Zhang H, Cui Z, Cheng D, Du Y, Guo X, Gao R, Chen J, Sun W, He R, Ma X, Peng Q, Martin BN, Yan W, Rong Y, Wang C. RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis. Autophagy 2020; 17:3030-3047. [PMID: 33280498 DOI: 10.1080/15548627.2020.1851496] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although genome-wide association studies have identified the gene RNF186 encoding an E3 ubiquitin-protein ligase as conferring susceptibility to ulcerative colitis, the exact function of this protein remains unclear. In the present study, we demonstrate an important role for RNF186 in macroautophagy/autophagy activation in colonic epithelial cells and intestinal homeostasis. Mechanistically, RNF186 acts as an E3 ubiquitin-protein ligase for EPHB2 and regulates the ubiquitination of EPHB2. Upon stimulation by ligand EFNB1 (ephrin B1), EPHB2 is ubiquitinated by RNF186 at Lys892, and further recruits MAP1LC3B for autophagy. Compared to control mice, rnf186-/- and ephb2-/- mice have a more severe phenotype in the DSS-induced colitis model, which is due to a defect in autophagy in colon epithelial cells. More importantly, treatment with ephrin-B1-Fc recombinant protein effectively relieves DSS-induced mouse colitis, which suggests that ephrin-B1-Fc may be a potential therapy for human inflammatory bowel diseases.Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; ATG16L1: autophagy related 16 like 1; ATP: adenosine triphosphate; Cas9: CRISPR associated protein 9; CD: Crohn disease; CQ: chloroquine; Csf2: colony stimulating factor 2; Cxcl1: c-x-c motif chemokine ligand 1; DMSO: dimethyl sulfoxide; DSS: dextran sodium sulfate; EFNB1: ephrin B1; EPHB2: EPH receptor B2; EPHB3: EPH receptor B3; EPHB2K788R: lysine 788 mutated to arginine in EPHB2; EPHB2K892R: lysine 892 mutated to arginine in EPHB2; ER: endoplasmic reticulum; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GWAS: genome-wide association studies; HRP: horseradish peroxidase; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IBD: inflammatory bowel diseases; Il1b: interleukin 1 beta; Il6: interleukin 6; IRGM:immunity related GTPase M; i.p.: intraperitoneally; IPP: inorganic pyrophosphatase; KD: knockdown; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NOD2: nucleotide binding oligomerization domain containing 2; PI3K: phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; RNF186: ring finger protein 186; RNF186A64T: alanine 64 mutated to threonine in RNF186; RNF186R179X: arginine 179 mutated to X in RNF186; RPS6: ribosomal protein S6; Tnf: tumor necrosis factor; SQSTM1: sequestosome 1; Ub: ubiquitin; UBE2D2: ubiquitin conjugating enzyme E2 D2; UBE2H: ubiquitin conjugating enzyme E2 H; UBE2K: ubiquitin conjugating enzyme E2 K; UBE2N: ubiquitin conjugating enzyme E2 N; UC: ulcerative colitis; ULK1:unc-51 like autophagy activating kinase 1; WT: wild type.
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Affiliation(s)
- Huazhi Zhang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihui Cui
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Du Cheng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yanyun Du
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Guo
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ru Gao
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Jianwen Chen
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Wanwei Sun
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ruirui He
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojian Ma
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Qianwen Peng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Bradley N Martin
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Yueguang Rong
- Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Chenhui Wang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.,Department of Bioinformatics, Wuhan Institute of Biotechnology, Wuhan, China
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Kim S, Lee JY, Shin SG, Kim JK, Silwal P, Kim YJ, Shin NR, Kim PS, Won M, Lee SH, Kim SY, Sasai M, Yamamoto M, Kim JM, Bae JW, Jo EK. ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota. Autophagy 2020; 17:2856-2875. [PMID: 33172329 DOI: 10.1080/15548627.2020.1847460] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The orphan nuclear receptor ESRRA (estrogen related receptor alpha) is critical in mitochondrial biogenesis and macroautophagy/autophagy function; however, the roles of ESRRA in intestinal function remain uncharacterized. Herein we identified that ESRRA acts as a key regulator of intestinal homeostasis by amelioration of colonic inflammation through activation of autophagic flux and control of host gut microbiota. Esrra-deficient mice presented with increased susceptibility to dextran sodium sulfate (DSS)-induced colitis with upregulation of intestinal inflammation. In addition, esrra-null mice had depressed AMP-activated protein kinase phosphorylation (AMPK), lower levels of TFEB (transcription factor EB), and accumulation of SQSTM1/p62 (sequestosome 1) with defective mitochondria in intestinal tissues. Esrra-deficient mice showed distinct gut microbiota composition and significantly higher microbial diversity than wild-type (WT) mice. Cohousing or fecal microbiota transplantation from WT mice to Esrra-deficient mice ameliorated DSS-induced colitis severity. Importantly, patients with ulcerative colitis (UC) had significantly decreased ESRRA expression in intestinal mucosal tissues that correlated with disease activity, suggesting clinical relevance of ESRRA in UC. Taken together, our results show that ESRRA contributes to intestinal homeostasis through autophagy activation and gut microbiota control to protect the host from detrimental inflammation and dysfunctional mitochondria.
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Affiliation(s)
- Sup Kim
- Department of Radiation Oncology, Chungnam National University Hospital, Daejeon, Korea
| | - June-Young Lee
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Dongdaemun-gu, Seoul, Korea
| | - Seul Gi Shin
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon Korea.,Infection Control Convergence Research Center, Chungnam National University School of Medicine Daejeon, Korea
| | - Jin Kyung Kim
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon Korea.,Infection Control Convergence Research Center, Chungnam National University School of Medicine Daejeon, Korea
| | - Prashanta Silwal
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon Korea.,Infection Control Convergence Research Center, Chungnam National University School of Medicine Daejeon, Korea
| | - Young Jae Kim
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon Korea.,Infection Control Convergence Research Center, Chungnam National University School of Medicine Daejeon, Korea
| | - Na-Ri Shin
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup, Korea
| | - Pil Soo Kim
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Dongdaemun-gu, Seoul, Korea
| | - Minho Won
- Biotechnology Process Engineering Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Chungcheongbuk-do Korea
| | - Sang-Hee Lee
- Center for Research Equipment, Korea Basic Science Institute, Chungbuk, Korea
| | - Soo Yeon Kim
- Future Medicine Division, Korea Institute of Oriental Medicine, Daejeon Korea
| | - Miwa Sasai
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka, Japan.,Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka Japan
| | - Masahiro Yamamoto
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka, Japan.,Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka Japan
| | - Jin-Man Kim
- Infection Control Convergence Research Center, Chungnam National University School of Medicine Daejeon, Korea.,Pathology and.,Department of Medical Science, Chungnam National University School of Medicine, Daejeon Korea
| | - Jin-Woo Bae
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Dongdaemun-gu, Seoul, Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon Korea.,Infection Control Convergence Research Center, Chungnam National University School of Medicine Daejeon, Korea
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48
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Khaloian S, Rath E, Hammoudi N, Gleisinger E, Blutke A, Giesbertz P, Berger E, Metwaly A, Waldschmitt N, Allez M, Haller D. Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn's disease recurrence. Gut 2020; 69:1939-1951. [PMID: 32111634 PMCID: PMC7569388 DOI: 10.1136/gutjnl-2019-319514] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 01/23/2020] [Accepted: 02/03/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Reduced Paneth cell (PC) numbers are observed in inflammatory bowel diseases and impaired PC function contributes to the ileal pathogenesis of Crohn's disease (CD). PCs reside in proximity to Lgr5+ intestinal stem cells (ISC) and mitochondria are critical for ISC-renewal and differentiation. Here, we characterise ISC and PC appearance under inflammatory conditions and describe the role of mitochondrial function for ISC niche-maintenance. DESIGN Ileal tissue samples from patients with CD, mouse models for mitochondrial dysfunction (Hsp60Δ/ΔISC) and CD-like ileitis (TNFΔARE), and intestinal organoids were used to characterise PCs and ISCs in relation to mitochondrial function. RESULTS In patients with CD and TNFΔARE mice, inflammation correlated with reduced numbers of Lysozyme-positive granules in PCs and decreased Lgr5 expression in crypt regions. Disease-associated changes in PC and ISC appearance persisted in non-inflamed tissue regions of patients with CD and predicted the risk of disease recurrence after surgical resection. ISC-specific deletion of Hsp60 and inhibition of mitochondrial respiration linked mitochondrial function to the aberrant PC phenotype. Consistent with reduced stemness in vivo, crypts from inflamed TNFΔARE mice fail to grow into organoids ex vivo. Dichloroacetate-mediated inhibition of glycolysis, forcing cells to shift to mitochondrial respiration, improved ISC niche function and rescued the ability of TNFΔARE mice-derived crypts to form organoids. CONCLUSION We provide evidence that inflammation-associated mitochondrial dysfunction in the intestinal epithelium triggers a metabolic imbalance, causing reduced stemness and acquisition of a dysfunctional PC phenotype. Blocking glycolysis might be a novel drug target to antagonise PC dysfunction in the pathogenesis of CD.
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Affiliation(s)
- Sevana Khaloian
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Eva Rath
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Nassim Hammoudi
- Department of Gastroenterology, Hôpital Saint-Louis, APHP, INSERM U1160, Université de Paris 1, Paris, Île-de-France, France
| | - Elisabeth Gleisinger
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Andreas Blutke
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Pieter Giesbertz
- Chair of Nutrition Physiology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Emanuel Berger
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Amira Metwaly
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Nadine Waldschmitt
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Matthieu Allez
- Department of Gastroenterology, Hôpital Saint-Louis, APHP, INSERM U1160, Université de Paris 1, Paris, Île-de-France, France
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany .,ZIEL Institute for Food & Health, Technische Universität München, München, Germany
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49
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Ardali R, Kazemipour N, Nazifi S, Bagheri Lankarani K, Razeghian Jahromi I, Sepehrimanesh M. Pathophysiological role of Atg5 in human ulcerative colitis. Intest Res 2020; 18:421-429. [PMID: 32380583 PMCID: PMC7609390 DOI: 10.5217/ir.2019.00120] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/19/2020] [Accepted: 01/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS Ulcerative colitis (UC), along with Crohn's disease, is one of the main types of inflammatory bowel disease (IBD). On the other hand, deregulated autophagy is involved in many chronic diseases, including IBD. In this study, we aimed to investigate the role of Atg5 and microRNA-181a (miR-181a) in the pathophysiology of UC. METHODS Colon biopsy, stool, and blood samples of 6 men and 9 women were confirmed for UC. Also, 13 men and 17 women were selected as healthy control (HC). Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to measure the Atg-5 content of the colon biopsies. Besides, the serum and stool levels of Atg5 were measured using ELISA. Moreover, the total RNA of blood cells was extracted and evaluated for the expression of miR-181a. RESULTS We found 1.2 ng/mL versus 0.46 ng/mL, 0.34 ng/mL versus 0.24 ng/mL, and 0.082 ng/mL versus 0.062 ng/mL of Atg5 in stool, intestinal tissue, and serum of UC and HCs, respectively. There was no significant difference in the expression of miR-181a in the blood samples of UC and HCs. Immunohistochemistry showed high positivity without any significant difference between the 2 groups in the quantitative analysis. CONCLUSIONS The significant difference observed between the stool Atg5 content of the HCs and UC patients may provide new insight into using this protein as a diagnostic biomarker, however, considering the small size of our studied population further studies are needed.
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Affiliation(s)
- Razieh Ardali
- Biochemistry Division, Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Nasrin Kazemipour
- Biochemistry Division, Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Saeed Nazifi
- Clinical Pathology Division, Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | | | | | - Masood Sepehrimanesh
- New Iberia Research Center, University of Louisiana at Lafayette, Lafayette, LA, USA
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50
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Rees WD, Stahl M, Jacobson K, Bressler B, Sly LM, Vallance BA, Steiner TS. Enteroids Derived From Inflammatory Bowel Disease Patients Display Dysregulated Endoplasmic Reticulum Stress Pathways, Leading to Differential Inflammatory Responses and Dendritic Cell Maturation. J Crohns Colitis 2020; 14:948-961. [PMID: 31796949 DOI: 10.1093/ecco-jcc/jjz194] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Endoplasmic reticulum [ER] stress in intestinal epithelial cells [IECs] contributes to the pathogenesis of inflammatory bowel disease [IBD]. We hypothesized that ER stress changes innate signalling in human IECs, augmenting toll-like receptor [TLR] responses and inducing pro-inflammatory changes in underlying dendritic cells [DCs]. METHODS Caco-2 cells and primary human colon-derived enteroid monolayers were exposed to ATP [control stressor] or thapsigargin [Tg] [ER stress inducer], and were stimulated with the TLR5 agonist flagellin. Cytokine release was measured by an enzyme immunoassay. ER stress markers CHOP, GRP78 and XBP1s/u were measured via quantitative PCR and Western blot. Monocyte-derived DCs [moDCs] were cultured with the IEC supernatants and their activation state was measured. Responses from enteroids derived from IBD patients and healthy control participants were compared. RESULTS ER stress enhanced flagellin-induced IL-8 release from Caco-2 cells and enteroids. Moreover, conditioned media activated DCs to become pro-inflammatory, with increased expression of CD80, CD86, MHCII, IL-6, IL-15 and IL-12p70 and decreased expression of CD103 and IL-10. Flagellin-induced IL-8 production correlated with DC activation, suggesting a common stress pathway. Moreover, there were distinct differences in cytokine expression and basal ER stress between IBD and healthy subject-derived enteroid monolayers, suggesting a dysregulated ER stress pathway in IBD-derived enteroids. CONCLUSIONS Cellular stress enhances TLR5 responses in IECs, leading to increased DC activation, indicating a previously unknown mechanistic link between epithelial ER stress and immune activation in IBD. Furthermore, dysregulated ER stress may be propagated from the intestinal epithelial stem cell niche in IBD patients.
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Affiliation(s)
- William D Rees
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada.,BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Martin Stahl
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Kevan Jacobson
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.,BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Brian Bressler
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada.,Providence Health, Vancouver, BC, Canada
| | - Laura M Sly
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.,BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Bruce A Vallance
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.,BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Theodore S Steiner
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.,BC Children's Hospital Research Institute, Vancouver, BC, Canada
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