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1
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Yang QH, Zhang CN. Comparative study on the pathogenesis of Crohn’s disease and ulcerative colitis. World J Gastroenterol 2025; 31:106406. [DOI: 10.3748/wjg.v31.i19.106406] [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: 02/25/2025] [Revised: 03/25/2025] [Accepted: 04/25/2025] [Indexed: 05/21/2025] Open
Abstract
Inflammatory bowel disease (IBD) is an incurable disease of the digestive system; however, the therapeutic methods for IBD remain limited. The pathogenesis of IBD was systematically discussed and compared in this paper, primarily comprising Crohn’s disease and ulcerative colitis. This paper focused on six common aspects: (1) Dysregulated immune responses; (2) Gene function changes; (3) Intestinal microbes disorder and imbalance; (4) Microbial infections; (5) Associations between IBD and other inflammatory diseases; and (6) Other factors. In addition, the pathogenesis differences between these two forms of IBD were unraveled and clearly distinguished. These unique aspects of pathogenesis provide crucial insights for the precise treatment of both Crohn’s disease and ulcerative colitis. This paper illustrates the root causes and beneficial factors of resistance to IBD, which provides novel insights on early prevention, development of new therapeutic agents, and treatment options of this disease.
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Affiliation(s)
- Qi-Hang Yang
- Chinese Academy of Medical Science & Peking Union Medical College, Institute of Biomedical Engineering, Tianjin 300192, China
- University College London, Cancer Institute, London WC1E 6BT, United Kingdom
| | - Chuang-Nian Zhang
- Chinese Academy of Medical Science & Peking Union Medical College, State Key Laboratory of Advanced Medical Materials and Devices, Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Tianjin Institutes of Health Science, Tianjin 300192, China
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2
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Dikovskaya D, Pemberton R, Taylor M, Tasegian A, Bhattacharya P, Zeneviciute K, Sammler EM, Howden AJM, Alessi DR, Swamy M. Inflammation and IL-4 regulate Parkinson's and Crohn's disease associated kinase LRRK2. EMBO Rep 2025:10.1038/s44319-025-00473-x. [PMID: 40394349 DOI: 10.1038/s44319-025-00473-x] [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: 08/14/2024] [Revised: 04/17/2025] [Accepted: 04/30/2025] [Indexed: 05/22/2025] Open
Abstract
Mutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and Crohn's disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we describe the development of a flow cytometry-based assay to assess LRRK2 activity in individual cells and the generation of an EGFP-Lrrk2 knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we measured LRRK2 levels and activity in murine splenic and intestinal immune cells and in human blood. Anti-CD3 induced inflammation increases LRRK2 expression and activity in B cells and monocytes, while in mature neutrophils, inflammation stimulates activity but reduces LRRK2 expression. A kinase-activating PD-associated LRRK2-R1441C mutation exacerbates inflammation-induced activation of LRRK2 specifically in monocytes and macrophages. We identify IL-4 as a novel T-cell-derived factor that upregulates LRRK2 expression and activity in B cells, replicating inflammatory effects observed in vivo. Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD.
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Affiliation(s)
- Dina Dikovskaya
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
- Peninsula Medical School, University of Plymouth, Drake Circus, Plymouth, PL4 8AA, UK.
| | - Rebecca Pemberton
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
| | - Matthew Taylor
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
- GlaxoSmithKline, Stevenage, UK
| | - Anna Tasegian
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
- Amphista Therapeutics Ltd., Granta Park, Great Abington, Cambridge, CB21 6GQ, UK
| | - Purbasha Bhattacharya
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
| | - Karolina Zeneviciute
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
| | - Esther M Sammler
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
- Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Andrew J M Howden
- Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
| | - Dario R Alessi
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
| | - Mahima Swamy
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
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3
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Tondi F, Cirsmaru RA, Conti C, Follenzi A, Gresele P, Olgasi C, Bury L. Hermansky-Pudlak Syndrome: From Molecular Pathogenesis to Targeted Therapies. IUBMB Life 2025; 77:e70025. [PMID: 40387003 PMCID: PMC12086961 DOI: 10.1002/iub.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/21/2025] [Accepted: 04/29/2025] [Indexed: 05/20/2025]
Abstract
Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder caused by defects in lysosome-related organelles (LROs) in various tissues, including platelets, melanocytes, and endothelial cells. Key features of HPS include oculocutaneous albinism, bleeding tendency, and, in some cases, pulmonary fibrosis, granulomatous colitis, and immunodeficiency. The condition is linked to mutations in 11 genes involved in the formation of LROs. Currently, treatment options for HPS are limited and often ineffective. Though cell and gene therapies have been explored for melanosomes and epithelial cells, there is limited knowledge about their application to platelets and endothelial cells. Understanding the detailed mechanisms of HPS pathogenesis is crucial, and using induced pluripotent stem cell (iPSC) models may provide valuable insights into the disease's molecular processes, aiding the development of new treatments. In this review, we will focus on the genetics and molecular mechanisms of HPS, on its clinical manifestations and current therapeutic approaches, highlighting the need for further research into the disease mechanisms and potential innovative therapies.
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Affiliation(s)
- Francesca Tondi
- Department of Medicine and Surgery, Section of Internal and Cardiovascular MedicineUniversity of PerugiaPerugiaItaly
| | | | - Chiara Conti
- Department of Medicine and Surgery, Section of Internal and Cardiovascular MedicineUniversity of PerugiaPerugiaItaly
| | - Antonia Follenzi
- Department of Health Sciences, School of MedicineUniversity of Piemonte OrientaleNovaraItaly
- Dipartimento Attività Integrate Ricerca InnovazioneAzienda Ospedaliero‐Universitaria SS. Antonio e Biagio e C. ArrigoAlessandriaItaly
| | - Paolo Gresele
- Department of Medicine and Surgery, Section of Internal and Cardiovascular MedicineUniversity of PerugiaPerugiaItaly
| | - Cristina Olgasi
- Department of Translational Medicine, School of MedicineUniversity of Piemonte OrientaleNovaraItaly
| | - Loredana Bury
- Department of Medicine and Surgery, Section of Internal and Cardiovascular MedicineUniversity of PerugiaPerugiaItaly
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4
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Chen T, Liu J, Hang R, Chen Q, Wang D. Neutrophils: From Inflammatory Bowel Disease to Colitis-Associated Colorectal Cancer. J Inflamm Res 2025; 18:925-947. [PMID: 39871958 PMCID: PMC11770381 DOI: 10.2147/jir.s497701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 01/06/2025] [Indexed: 01/29/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a non-specific inflammatory disease of digestive tract, primarily manifesting as ulcerative colitis (UC) and Crohn's disease (CD). The precise etiology of IBD remains elusive. The interplay of genetic factors, environmental influences, and intestinal microbiota contributes to the establishment of an uncontrolled immune environment within the intestine, which can progressively lead to atypical hyperplasia and ultimately to malignancy over a long period. This colorectal malignant tumor that arises from chronic IBD is referred to as colitis-associated colorectal cancer (CAC). Dysregulation in the quantity and functionality of neutrophils plays a significant role in the onset, progression, and recurrence of IBD, as well as in the transition from IBD to CAC. Neutrophils affect the pathophysiology of IBD through various mechanisms, including the production of reactive oxygen species (ROS), degranulation, the release of inflammatory mediators and chemokines, and the formation of neutrophil extracellular traps (NETs). These processes can induce DNA mutations, thereby facilitating the development of colon cancer. Given the incomplete understanding of the disease mechanisms underlying IBD and CAC, effective treatment and prevention strategies remain challenging. Consequently, a comprehensive review of the functional roles of neutrophils in IBD and CAC is essential for advancing our understanding of IBD pathogenesis and identifying potential therapeutic targets.
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Affiliation(s)
- Tianyi Chen
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Jiachen Liu
- Radiology Department, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Ruyi Hang
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Qian Chen
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Dong Wang
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
- Oncology Department of Qianjiang Center Hospital, Chongqing University, Chongqing, People’s Republic of China
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5
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Yin R, Wang T, Sun J, Dai H, Zhang Y, Liu N, Liu H. Postbiotics From Lactobacillus Johnsonii Activates Gut Innate Immunity to Mitigate Alcohol-Associated Liver Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2405781. [PMID: 39574408 PMCID: PMC11727117 DOI: 10.1002/advs.202405781] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 10/10/2024] [Indexed: 01/14/2025]
Abstract
Prolonged alcohol consumption disrupts the gut microbiota and the immune system, contributing to the pathogenesis of alcohol-associated liver disease (ALD). Probiotic-postbiotic intervention strategies can effectively relieve ALD by maintaining gut homeostasis. Herein, the efficacy of heat-killed Lactobacillus johnsonii (HKLJ) in mitigating alcoholic liver damage is demonstrated in mouse models of ALD. The gut-liver axis is identified as a pivotal pathway for the protective effects of L. johnsonii against ALD. Specifically, HKLJ is found to upregulate the expression of intestinal lysozymes, thereby enhancing the production of immunoregulatory substances from gut bacteria, which subsequently activated the Nucleotide-binding oligomerization domain 2 (NOD2)-interleukin (IL-23)-IL-22 innate immune axis. The elevated IL-22 upregulated the antimicrobial peptide synthesis to maintain intestinal homeostasis and moreover activated the Signal transducer and activator of Transcription3 (STAT3) pathway in the liver to facilitate the repair of hepatic injuries. The heat-killed L. johnsonii provoked immunity helps correct the gut microbiota dysbiosis, specifically by reversing the reduction of butyrate-producing bacteria (such as Faecalibaculum rodentium) and the expansion of opportunistic pathogens (such as Helicobacter sp. and Pichia kudriavzevii) induced by ethanol. The findings provide novel insights into the gut microbiota-liver axis that may be leveraged to enhance the treatment of ALD.
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Affiliation(s)
- Ruopeng Yin
- State Key Laboratory of MycologyInstitute of MicrobiologyChinese Academy of SciencesBeijing100101China
- Medical SchoolUniversity of Chinese Academy of SciencesBeijing100049China
| | - Tao Wang
- State Key Laboratory of MycologyInstitute of MicrobiologyChinese Academy of SciencesBeijing100101China
| | - Jingzu Sun
- State Key Laboratory of MycologyInstitute of MicrobiologyChinese Academy of SciencesBeijing100101China
| | - Huanqin Dai
- State Key Laboratory of MycologyInstitute of MicrobiologyChinese Academy of SciencesBeijing100101China
- Medical SchoolUniversity of Chinese Academy of SciencesBeijing100049China
| | - Yuting Zhang
- State Key Laboratory of MycologyInstitute of MicrobiologyChinese Academy of SciencesBeijing100101China
- Medical SchoolUniversity of Chinese Academy of SciencesBeijing100049China
| | - Ningning Liu
- CAS Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of MicrobiologyChinese Academy of SciencesBeijing100101China
| | - Hongwei Liu
- State Key Laboratory of MycologyInstitute of MicrobiologyChinese Academy of SciencesBeijing100101China
- Medical SchoolUniversity of Chinese Academy of SciencesBeijing100049China
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6
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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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Wallings RL, McFarland K, Staley HA, Neighbarger N, Schaake S, Brüggemann N, Zittel S, Usnich T, Klein C, Sammler EM, Tansey MG. The R1441C-Lrrk2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice. Sci Transl Med 2024; 16:eadl1535. [PMID: 39504353 DOI: 10.1126/scitranslmed.adl1535] [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: 10/12/2023] [Revised: 01/19/2024] [Accepted: 10/17/2024] [Indexed: 11/08/2024]
Abstract
Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the LRRK2 gene affects risk for both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from R1441C-Lrrk2 knock-in mice and observed a biphasic, age-dependent effect of the R1441C-Lrrk2 mutation on peritoneal macrophage function. We report increases in antigen presentation, anti-inflammatory cytokine production, lysosomal activity, and pathogen uptake in peritoneal macrophages from young (2- to 3-month-old) female R1441C-Lrrk2 mice. Conversely, macrophages from aged (18- to 21-month-old) female R1441C-Lrrk2 mice exhibited decreased antigen presentation after inflammatory insult, decreased lysosomal function, and pathogen uptake, with a concomitant increase in DNA fragmentation in the presence of pathogens. This immune cell exhaustion phenotype was not observed in male R1441C-Lrrk2 mice and was driven by increased LRRK2 protein kinase activity. This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the R1441C- or Y1699C-LRRK2 mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.
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Affiliation(s)
- Rebecca L Wallings
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Karen McFarland
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
- Department of Neurology and Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA
- Department of Pharmacology, Emory University, Atlanta, GA, USA
| | - Hannah A Staley
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
| | - Noelle Neighbarger
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
| | - Susen Schaake
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Norbert Brüggemann
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simone Zittel
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tatiana Usnich
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Klein
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Esther M Sammler
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
- Department of Neurology, School of Medicine, Ninewells Hospital, Ninewells Drive, Dundee DD1 9SY, UK
| | - Malú Gámez Tansey
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
- Department of Neurology and Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA
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Tasegian A, Dikovskaya D, Scott MM, Chawla AS, Pemberton R, Helps T, Meus T, McLean MH, Swamy M. LRRK2 is not required for lysozyme expression in Paneth cells. Nat Immunol 2024; 25:2037-2039. [PMID: 39379660 DOI: 10.1038/s41590-024-01972-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 09/06/2024] [Indexed: 10/10/2024]
Affiliation(s)
- Anna Tasegian
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
- Amphista Therapeutics, Cambridge, UK
| | - Dina Dikovskaya
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Molly M Scott
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, UK
| | - Amanpreet Singh Chawla
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Rebecca Pemberton
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Thomas Helps
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, UK
| | - Tosca Meus
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Mairi H McLean
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, UK
| | - Mahima Swamy
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
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9
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Zhang C, Han L, Dong K, Zhang Q, Liu Z. Reply to: LRRK2 is not required for lysozyme expression in Paneth cells. Nat Immunol 2024; 25:2040-2042. [PMID: 39379659 DOI: 10.1038/s41590-024-01968-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 08/29/2024] [Indexed: 10/10/2024]
Affiliation(s)
- Chengye Zhang
- Institute of Immunology, School of Basic Medicine, Tsinghua University, Beijing, China
| | - Lizhuang Han
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Kemeng Dong
- Institute of Immunology, School of Basic Medicine, Tsinghua University, Beijing, China
| | - Qin Zhang
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
| | - Zhihua Liu
- Institute of Immunology, School of Basic Medicine, Tsinghua University, Beijing, China.
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10
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Li Y, Liu X, Sun X, Li H, Wang S, Tian W, Xiang C, Zhang X, Zheng J, Wang H, Zhang L, Cao L, Wong CCL, Liu Z. Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration. Protein Cell 2024; 15:818-839. [PMID: 38635907 PMCID: PMC11528516 DOI: 10.1093/procel/pwae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/05/2024] [Indexed: 04/20/2024] Open
Abstract
Scavenger receptor class B, member 2 (SCARB2) is linked to Gaucher disease and Parkinson's disease. Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy (PME), a rare group of inherited neurodegenerative diseases characterized by myoclonus. We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption, accompanied with vitamin E deficiency. Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool, leading to hyperactivation of FXR in intestine. Hyperactivation of FXR impairs epithelium renewal and lipid absorption. Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E. Finally, inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice. These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration, and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.
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Affiliation(s)
- Yinghui Li
- Institute for Immunology and School of Basic Medicine, Tsinghua University, Beijing 100084, China
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xingchen Liu
- Institute for Immunology and School of Basic Medicine, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xue Sun
- First School of Clinical Medicine, Peking University First Hospital, Peking University, Beijing 100034, China
- School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, United States
| | - Hui Li
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shige Wang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Wotu Tian
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Chen Xiang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuyuan Zhang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiajia Zheng
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, 100191, China
| | - Haifang Wang
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
| | - Liguo Zhang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Li Cao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Catherine C L Wong
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
- Tsinghua University-Peking University Joint Center for Life Sciences, Peking University, Beijing 100084, China
| | - Zhihua Liu
- Institute for Immunology and School of Basic Medicine, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
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11
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Haynes J, Palaniappan B, Crutchley JM, Sundaram U. Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers. Cells 2024; 13:1623. [PMID: 39404387 PMCID: PMC11482628 DOI: 10.3390/cells13191623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
In the small intestine, sodium (Na) absorption occurs primarily via two apical transporters, Na-hydrogen exchanger 3 (NHE3) and Na-glucose cotransporter 1 (SGLT1). The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells. However, whether NHE3 and SGLT1 regulate one another in normal human enterocytes is unknown, mainly due to a lack of appropriate experimental models. To investigate this, we generated 2D enterocyte monolayers from human jejunal 3D organoids and used small interfering RNAs (siRNAs) to knock down NHE3 or SGLT1. Molecular and uptake studies were performed to determine the effects on NHE3 and SGLT1 expression and activity. Knockdown of NHE3 by siRNA in enterocyte monolayers was verified by qPCR and Western blot analysis and resulted in reduced NHE3 activity. However, in NHE3 siRNA-transfected cells, SGLT1 activity was significantly increased. siRNA knockdown of SGLT1 was confirmed by qPCR and Western blot analysis and resulted in reduced SGLT1 activity. However, in SGLT1 siRNA-transfected cells, NHE3 activity was significantly increased. These results demonstrate for the first time the functionality of siRNA in patient-derived organoid monolayers. Furthermore, they show that the two primary Na absorptive pathways in human enterocytes reciprocally regulate one another.
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Affiliation(s)
| | | | | | - Uma Sundaram
- Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA
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12
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Saki N, Hadi H, Keikhaei B, Mirzaei A, Purrahman D. Gut microbiome composition and dysbiosis in immune thrombocytopenia: A review of literature. Blood Rev 2024; 67:101219. [PMID: 38862311 DOI: 10.1016/j.blre.2024.101219] [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: 02/16/2024] [Revised: 04/14/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by excessive reticuloendothelial platelet destruction and inadequate compensatory platelet production. However, the pathogenesis of ITP is relatively complex, and its exact mechanisms and etiology have not been definitively established. The gut microbiome, namely a diverse community of symbiotic microorganisms residing in the gastrointestinal system, affects health through involvement in human metabolism, immune modulation, and maintaining physiological balance. Emerging evidence reveals that the gut microbiome composition differs in patients with ITP compared to healthy individuals, which is related with platelet count, disease duration, and response to treatment. These findings suggest that the microbiome and metabolome profiles of individuals could unveil a new pathway for aiding diagnosis, predicting prognosis, assessing treatment response, and formulating personalized therapeutic approaches for ITP. However, due to controversial reports, definitive conclusions cannot be drawn, and further investigations are needed.
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Affiliation(s)
- Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hakimeh Hadi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Bijan Keikhaei
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Arezoo Mirzaei
- Department of Bacteriology and Virology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Daryush Purrahman
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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13
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Zhang W, Zou M, Fu J, Xu Y, Zhu Y. Autophagy: A potential target for natural products in the treatment of ulcerative colitis. Biomed Pharmacother 2024; 176:116891. [PMID: 38865850 DOI: 10.1016/j.biopha.2024.116891] [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: 01/24/2024] [Revised: 05/16/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the mucosa of the colon and rectum. UC is characterized by recurrent episodes, often necessitating lifelong medication use, imposing a significant burden on patients. Current conventional and advanced treatments for UC have the disadvantages of insufficient efficiency, susceptibility to drug resistance, and notable adverse effects. Therefore, developing effective and safe drugs has become an urgent need. Autophagy is an intracellular degradation process that plays an important role in intestinal homeostasis. Emerging evidence suggests that aberrant autophagy is involved in the development of UC, and modulating autophagy can effectively alleviate experimental colitis. A growing number of studies have established that autophagy can interplay with endoplasmic reticulum stress, gut microbiota, apoptosis, and the NLRP3 inflammasome, all of which contribute to the pathogenesis of UC. In addition, a variety of intestinal epithelial cells, including absorptive cells, goblet cells, and Paneth cells, as well as other cell types like neutrophils, antigen-presenting cells, and stem cells in the gut, mediate the development of UC through autophagy. To date, many studies have found that natural products hold the potential to exert therapeutic effects on UC by regulating autophagy. This review focuses on the possible effects and pharmacological mechanisms of natural products to alleviate UC with autophagy as a potential target in recent years, aiming to provide a basis for new drug development.
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Affiliation(s)
- Wei Zhang
- The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Menglong Zou
- The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jia Fu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Yin Xu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
| | - Ying Zhu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
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14
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Han J, Balasubramanian I, Flores JA, Bandyopadhyay S, Yang J, Liu Y, Singh R, Setty P, Kiela P, Ferraris R, Gao N. Intestinal lysozyme engagement of Salmonella Typhimurium stimulates the release of barrier-impairing InvE and Lpp1. J Biol Chem 2024; 300:107424. [PMID: 38823640 PMCID: PMC11255904 DOI: 10.1016/j.jbc.2024.107424] [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: 02/28/2024] [Revised: 05/06/2024] [Accepted: 05/17/2024] [Indexed: 06/03/2024] Open
Abstract
Lysozyme is a β-1,4-glycosidase that hydrolyzes the polysaccharide backbone of bacterial cell walls. With an additional bactericidal function mediated by a separate protein domain, lysozyme is considered a uniquely important antimicrobial molecule contributing to the host's innate immune response to infection. Elevated lysozyme production is found in various inflammatory conditions while patients with genetic risks for inflammatory bowel diseases demonstrate abnormal lysozyme expression, granule packaging, and secretion in Paneth cells. However, it remains unclear how a gain- or loss-of-function in host lysozyme may impact the host inflammatory responses to pathogenic infection. We challenged Lyz1-/- and ectopic Lyz1-expressing (Villin-Lyz1TG) mice with S. Typhimurium and then comprehensively assessed the inflammatory disease progression. We conducted proteomics analysis to identify molecules derived from human lysozyme-mediated processing of live Salmonella. We examined the barrier-impairing effects of these identified molecules in human intestinal epithelial cell monolayer and enteroids. Lyz1-/- mice are protected from infection in terms of morbidity, mortality, and barrier integrity, whereas Villin-Lyz1TG mice demonstrate exacerbated infection and inflammation. The growth and invasion of Salmonella in vitro are not affected by human or chicken lysozyme, whereas lysozyme encountering of live Salmonella stimulates the release of barrier-disrupting factors, InvE-sipC and Lpp1, which directly or indirectly impair the tight junctions. The direct engagement of host intestinal lysozyme with an enteric pathogen such as Salmonella promotes the release of virulence factors that are barrier-impairing and pro-inflammatory. Controlling lysozyme function may help alleviate the inflammatory progression.
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Affiliation(s)
- Jiangmeng Han
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | | | - Juan A Flores
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | | | - Jiaxing Yang
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | - Yue Liu
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | - Rajbir Singh
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | - Prashanth Setty
- Department of Pediatrics, Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children's Research Center, University of Arizona, Tucson, Arizona, USA
| | - Pawel Kiela
- Department of Pediatrics, Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children's Research Center, University of Arizona, Tucson, Arizona, USA
| | - Ronaldo Ferraris
- Department of Pharmacology, Physiology, and Neuroscience, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA; Department of Pharmacology, Physiology, and Neuroscience, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.
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15
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Peng Z, Zhang J, Zhang M, Yin L, Zhou Z, Lv C, Wang Z, Tang J. Tryptophan metabolites relieve intestinal Candida albicans infection by altering the gut microbiota to reduce IL-22 release from group 3 innate lymphoid cells of the colon lamina propria. Food Funct 2024; 15:5364-5381. [PMID: 38639049 DOI: 10.1039/d4fo00432a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
Invasive candidiasis may be caused by Candida albicans (C. albicans) colonization of the intestinal tract. Preventing intestinal damage caused by Candida albicans infection and protecting intestinal barrier function have become a critical issue. Integrated analyses of the microbiome with metabolome revealed a remarkable shift of the gut microbiota and tryptophan metabolites, kynurenic acid (KynA), and indolacrylic acid (IA) in mice infected with C. albicans. The transcriptome sequencing indicated that differentially expressed genes were significantly associated with innate immune responses and inflammatory responses. The results of this study suggest that KynA and IA (KI) can alleviate intestinal damage caused by Candida albicans infection in mice by reducing intestinal permeability, increasing intestinal firmness, alleviating intestinal inflammation, and reducing the secretion of interleukin-22 (IL-22) in the 3 groups of colon innate lymphoid cells (ILC3). We performed a fecal microbiota transplantation (FMT) experiment and found that the intestinal barrier function, inflammation, and IL-22 secretion of ILC3 in the colon lamina propria of the recipient mice subjected to C. albicans infection and KI treatment were consistent with the trends of the donor mice. Our results suggest that tryptophan metabolites may directly regulate colon lamina ILC3 to promote intestinal resistance to C. albicans invasion, or indirectly regulate the ILC3 secretion of IL-22 to play a protective role in the intestinal barrier by affecting intestinal microorganisms, which may become a potential target for alleviating intestine borne C. albicans infection.
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Affiliation(s)
- Ziyao Peng
- Department of Trauma-Emergency and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Jiali Zhang
- Central Laboratory, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Meng Zhang
- Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Liping Yin
- Department of Trauma-Emergency and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Ziyang Zhou
- Department of Trauma-Emergency and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Cuiting Lv
- Central Laboratory, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Zetian Wang
- Department of Trauma-Emergency and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Jianguo Tang
- Department of Trauma-Emergency and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
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16
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Wallings R, McFarland K, Staley H, Neighbarger N, Schaake S, Brueggemann N, Zittel S, Usnich T, Klein C, Sammler E, Tansey MG. The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.10.12.562063. [PMID: 37905053 PMCID: PMC10614788 DOI: 10.1101/2023.10.12.562063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.
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17
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Zheng Z, Zhang S, Liu X, Wang X, Xue C, Wu X, Zhang X, Xu X, Liu Z, Yao L, Lu G. LRRK2 regulates ferroptosis through the system Xc-GSH-GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease. J Cell Physiol 2024; 239:e31250. [PMID: 38477420 DOI: 10.1002/jcp.31250] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/24/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024]
Abstract
Parkinson's disease (PD) is the most prevalent neurodegenerative disorder. Neuroinflammation mediated by activated microglia and apoptosis of dopaminergic (DA) neurons in the midbrain are its primary pathological manifestations. Leucine-rich repeat protein kinase 2 (LRRK2) kinase has been observed to increase expression during neuroinflammation, however, the effect of LRRK2 on microglia activation remains poorly understood. In this study, we have established lipopolysaccharide (LPS) treated BV2 cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models for both in vivo and in vitro investigation. Our data in vivo reveal that LRRK2 can promote microglia activation by regulating ferroptosis and activating nuclear factor-κB. Inhibition of LRRK2 expression effectively suppressed the LPS-induced pro-inflammatory cytokines and facilitated the secretion of neuroprotective factors. Importantly, by co-overexpressing LRRK2 and glutathione peroxidase 4 (GPX4), we identified the system Xc-GSH-GPX4 pathway as a crucial component in LRRK2-mediated microglial ferroptosis and inflammatory responses. Using a microglial culture supernatant (MCS) transfer model, we found that inhibiting LRRK2 or downregulating ferroptosis in BV2 cells prevented SH-SY5Y cell apoptosis. Additionally, we observed abundant expression of LRRK2 and P-P65 in the midbrain, which was elevated in the MPTP-induced PD model, along with microglia activation. LRRK2 and P-P65 expression inhibition with PF-06447475 attenuated microglia activation in the nigrostriatal dense part of MPTP-treated mice. Based on our findings, it is evident that LRRK2 plays a critical role in promoting the neuroinflammatory response during the pathogenesis of PD by regulating the system Xc-GSH-GPX4 pathway. Taken together, our data highlights the potential research and therapeutic value of targeting LRRK2 to regulate neuroinflammatory response in PD through ferroptosis.
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Affiliation(s)
- Zijian Zheng
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Shushan Zhang
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinjie Liu
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiangrong Wang
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Cheng Xue
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiao Wu
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinran Zhang
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinping Xu
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zheng Liu
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Longping Yao
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Department of Neuroanatomy, Group for Regeneration and Reprogramming, Institute for Regeneration, Anatomy and Cel Biology, Medical Faculty, Heidelberg University, Heidelberg, Germany
| | - Guohui Lu
- Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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18
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Guo L, Liu Q, Yin X. Clostridiales in the Gut Against Listeria monocytogenes Infection Through Growth Inhibition. Foodborne Pathog Dis 2024; 21:248-256. [PMID: 38150235 DOI: 10.1089/fpd.2023.0049] [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] [Indexed: 12/28/2023] Open
Abstract
Listeria monocytogenes (Lm) mainly infect pregnant women, children, the elderly, and other populations with low immunity causing septicemia and meningitis. Healthy people can tolerate higher doses of Lm and only cause gastrointestinal symptoms such as abdominal pain and diarrhea after infection. Compared to the above population, healthy people have a richer and more diverse gut microbiota. In this study, we show that the microbiota in the large intestine and the feces of mice can significantly inhibit the growth of Lm compared to the microbiota in the small intestine. Bacteria larger than 1 μm in the gut microbiota play an important role in inhibiting Lm growth. 16s rRNA sequencing results show that these bacteria are mainly composed of Clostridiales under the phylum Firmicutes, including Ruminiclostridium, Butyricicoccus, Lachnoclostridium, Roseburia, Coprooccus, and Blautia. Thus, we demonstrate that there are some potential functional bacteria in the gut microbiota that can increase resistance against Lm.
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Affiliation(s)
- Liang Guo
- Zaozhuang University, Shandong, China
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Qing Liu
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China
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19
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Zhang Q, Wang X, Zheng J, Lü Q, Li R, Jia X, Gu M. Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1 correlate with Crohn's disease. Heliyon 2024; 10:e22968. [PMID: 38163100 PMCID: PMC10754897 DOI: 10.1016/j.heliyon.2023.e22968] [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] [Received: 01/13/2023] [Revised: 11/12/2023] [Accepted: 11/22/2023] [Indexed: 01/03/2024] Open
Abstract
To identify candidate pathogenic genes of early-stage Crohn's disease (CD) and predict potential roles of genetic factors in CD, we performed whole exome sequencing on a child with early-stage Crohn's disease (CD) and her parents (core family), found that the patient carried heterozygous variants of 4 genes: NOD2 c. 2257 C > T, IL10RA c. 301 C > T, PLA2G6 c. 2029 C > T, COL7A1 c. 3190 G > A. Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1, intestinal inflammatory response is triggered, normal intestinal wall tissue damage, leading to CD phenotype.
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Affiliation(s)
| | | | | | - Qiang Lü
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
| | - Rongrong Li
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
| | - Xiaodong Jia
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
| | - Mingliang Gu
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
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20
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Mercado G, Kaeufer C, Richter F, Peelaerts W. Infections in the Etiology of Parkinson's Disease and Synucleinopathies: A Renewed Perspective, Mechanistic Insights, and Therapeutic Implications. JOURNAL OF PARKINSON'S DISEASE 2024; 14:1301-1329. [PMID: 39331109 PMCID: PMC11492057 DOI: 10.3233/jpd-240195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/06/2024] [Indexed: 09/28/2024]
Abstract
Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies.
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Affiliation(s)
- Gabriela Mercado
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christopher Kaeufer
- Center for Systems Neuroscience, Hannover, Germany
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Franziska Richter
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Wouter Peelaerts
- Laboratory for Virology and Gene Therapy, Department of Pharmacy and Pharmaceutical Sciences, KU Leuven, Leuven, Belgium
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21
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Peng HR, Qiu JQ, Zhou QM, Zhang YK, Chen QY, Yin YQ, Su W, Yu S, Wang YT, Cai Y, Gu MN, Zhang HH, Sun QQ, Hu G, Wu YW, Liu J, Chen S, Zhu ZJ, Song XY, Zhou JW. Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis. Immunity 2023; 56:2773-2789.e8. [PMID: 37992711 DOI: 10.1016/j.immuni.2023.10.016] [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: 03/13/2023] [Revised: 08/22/2023] [Accepted: 10/27/2023] [Indexed: 11/24/2023]
Abstract
Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.
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Affiliation(s)
- Hai-Rong Peng
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jia-Qian Qiu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China
| | - Qin-Ming Zhou
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yu-Kai Zhang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Qiao-Yu Chen
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yan-Qing Yin
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Wen Su
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shui Yu
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ya-Ting Wang
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuping Cai
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China
| | - Ming-Na Gu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Hao-Hao Zhang
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Qing-Qing Sun
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Gang Hu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yi-Wen Wu
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Liu
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Sheng Chen
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Zheng-Jiang Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China.
| | - Xin-Yang Song
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
| | - Jia-Wei Zhou
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China; Innovation Center of Neurodegeneration, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China.
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22
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Wallings RL, Mark JR, Staley HA, Gillett DA, Neighbarger N, Kordasiewicz H, Hirst WD, Tansey MG. ASO-mediated knockdown or kinase inhibition of G2019S-Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 34:102064. [PMID: 38028198 PMCID: PMC10661462 DOI: 10.1016/j.omtn.2023.102064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023]
Abstract
Genetic variation around the LRRK2 gene affects risk for both familial and sporadic Parkinson's disease (PD). LRRK2 levels have become an appealing target for potential PD therapeutics with LRRK2 antisense oligonucleotides (ASOs) now moving toward clinical trials. However, LRRK2 has been suggested to play a fundamental role in peripheral immunity, and it is currently unknown if targeting increased LRRK2 levels in peripheral immune cells will be beneficial or deleterious. Here it was observed that G2019S macrophages exhibited increased stimulation-dependent lysosomal tubule formation (LTF) and MHC-II trafficking from the perinuclear lysosome to the plasma membrane in an mTOR-dependent manner with concomitant increases in pro-inflammatory cytokine release. Both ASO-mediated knockdown of mutant Lrrk2 and LRRK2 kinase inhibition ameliorated this phenotype and decreased these immune responses in control cells. Given the critical role of antigen presentation, lysosomal function, and cytokine release in macrophages, it is likely LRRK2-targeting therapies with systemic activity may have therapeutic value with regard to mutant LRRK2, but deleterious effects on the peripheral immune system, such as altered pathogen control in these cells, should be considered when reducing levels of non-mutant LRRK2.
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Affiliation(s)
- Rebecca L. Wallings
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
| | - Julian R. Mark
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
| | - Hannah A. Staley
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
| | - Drew A. Gillett
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
| | - Noelle Neighbarger
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
| | - Holly Kordasiewicz
- Neurology, Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - Warren D. Hirst
- Neurodegenerative Diseases Research Unit, Biogen, 115 Broadway, Cambridge, MA 02142, USA
| | - Malú Gámez Tansey
- Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
- Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL 32610, USA
- Department of Neurology and Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL 32608, USA
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23
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Balasubramanian I, Bandyopadhyay S, Flores J, Bianchi‐Smak J, Lin X, Liu H, Sun S, Golovchenko NB, Liu Y, Wang D, Patel R, Joseph I, Suntornsaratoon P, Vargas J, Green PHR, Bhagat G, Lagana SM, Ying W, Zhang Y, Wang Z, Li WV, Singh S, Zhou Z, Kollias G, Farr LA, Moonah SN, Yu S, Wei Z, Bonder EM, Zhang L, Kiela PR, Edelblum KL, Ferraris R, Liu T, Gao N. Infection and inflammation stimulate expansion of a CD74 + Paneth cell subset to regulate disease progression. EMBO J 2023; 42:e113975. [PMID: 37718683 PMCID: PMC10620768 DOI: 10.15252/embj.2023113975] [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: 03/08/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 09/19/2023] Open
Abstract
Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.
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Affiliation(s)
| | | | - Juan Flores
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | | | - Xiang Lin
- Department of Computer ScienceNew Jersey Institute of TechnologyNewarkNJUSA
| | - Haoran Liu
- Department of Computer ScienceNew Jersey Institute of TechnologyNewarkNJUSA
| | - Shengxiang Sun
- Department of Pathology and ImmunologyWashington University School of MedicineSaint LouisMOUSA
| | | | - Yue Liu
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Dahui Wang
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Radha Patel
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Ivor Joseph
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Panan Suntornsaratoon
- Department of Pharmacology, Physiology & NeuroscienceRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Justin Vargas
- Department of Medicine, Celiac Disease CenterColumbia University Irving Medical CenterNew YorkNYUSA
| | - Peter HR Green
- Department of Medicine, Celiac Disease CenterColumbia University Irving Medical CenterNew YorkNYUSA
| | - Govind Bhagat
- Department of Medicine, Celiac Disease CenterColumbia University Irving Medical CenterNew YorkNYUSA
- Department of Pathology and Cell BiologyColumbia University Irving Medical CenterNew YorkNYUSA
| | - Stephen M Lagana
- Department of Pathology and Cell BiologyColumbia University Irving Medical CenterNew YorkNYUSA
| | - Wang Ying
- Hackensack Meridian Health Center for Discovery and InnovationNutleyNJUSA
| | - Yi Zhang
- Hackensack Meridian Health Center for Discovery and InnovationNutleyNJUSA
| | - Zhihan Wang
- Department of StatisticsRutgers UniversityNew BrunswickNJUSA
| | - Wei Vivian Li
- Department of Biostatistics and EpidemiologyRutgers UniversityNew BrunswickNJUSA
| | - Sukhwinder Singh
- Department of PathologyRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Zhongren Zhou
- Department of Pathology & Laboratory Medicine, Robert Wood Johnson Medical SchoolRutgers UniversityNew BrunswickNJUSA
| | - George Kollias
- Biomedical Sciences Research Centre, “Alexander Fleming”VariGreece
| | - Laura A Farr
- Division of Infectious Diseases and International HealthUniversity of VirginiaCharlottesvilleVAUSA
| | - Shannon N Moonah
- Division of Infectious Diseases and International HealthUniversity of VirginiaCharlottesvilleVAUSA
| | - Shiyan Yu
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Zhi Wei
- Department of Computer ScienceNew Jersey Institute of TechnologyNewarkNJUSA
| | - Edward M Bonder
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Lanjing Zhang
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
- Department of PathologyPenn Medicine Princeton Medical CenterPlainsboroNJUSA
| | - Pawel R Kiela
- Departments of Pediatrics and Immunology, and Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children's Research CenterThe University of Arizona Health SciencesTucsonAZUSA
| | - Karen L Edelblum
- Center for Immunity and InflammationRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Ronaldo Ferraris
- Department of Pharmacology, Physiology & NeuroscienceRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Ta‐Chiang Liu
- Department of Pathology and ImmunologyWashington University School of MedicineSaint LouisMOUSA
| | - Nan Gao
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
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24
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de Guilhem de Lataillade A, Pellegrini C, Neunlist M, Rolli-Derkinderen M, Derkinderen P. Are LRRK2 mysteries lurking in the gut? Am J Physiol Gastrointest Liver Physiol 2023; 325:G429-G435. [PMID: 37643021 DOI: 10.1152/ajpgi.00162.2023] [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] [Received: 07/31/2023] [Revised: 08/23/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023]
Abstract
Gut-brain axis and inflammation are two hot topics in Parkinson's disease (PD). In this setting, the leucine-rich repeat kinase 2 (LRRK2) gene, which encodes the eponym protein, has attracted much attention. LRRK2 is not only the gene most commonly associated with Parkinson's disease but also a susceptibility gene for Crohn's disease (CD), thereby suggesting that it may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. In contrast to the accumulated data on LRRK2 in the central nervous system (CNS), research on LRRK2 in the digestive tract is still in its infancy, and the scope of the present review article is therefore to review existing studies on LRRK2 in the gastrointestinal tract in both physiological and pathological conditions. In light of current data on LRRK2 in the gastrointestinal tract, we discuss if LRRK2 could be or not regarded as a molecular link between gut inflammation, Parkinson's disease, and Crohn's disease, and we suggest directions for future research.
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Affiliation(s)
- Adrien de Guilhem de Lataillade
- The Enteric Nervous System In Gut And Brain Disorders, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, Nantes, France
| | - Carolina Pellegrini
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Michel Neunlist
- The Enteric Nervous System In Gut And Brain Disorders, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, Nantes, France
| | - Malvyne Rolli-Derkinderen
- The Enteric Nervous System In Gut And Brain Disorders, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, Nantes, France
| | - Pascal Derkinderen
- The Enteric Nervous System In Gut And Brain Disorders, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, Nantes, France
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25
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Chauvin C, Radulovic K, Boulard O, Delacre M, Waldschmitt N, Régnier P, Legris G, Bouchez C, Sleimi MY, Rosenstiel P, Darrasse-Jèze G, Chamaillard M, Poulin LF. Loss of NOD2 in macrophages improves colitis and tumorigenesis in a lysozyme-dependent manner. Front Immunol 2023; 14:1252979. [PMID: 37876927 PMCID: PMC10590911 DOI: 10.3389/fimmu.2023.1252979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/14/2023] [Indexed: 10/26/2023] Open
Abstract
Background Crohn's disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the NOD2 gene confer an increased susceptibility to ileal CD. While Nod2 in myeloid cells may confer protection against T-cell mediated ileopathy, it remains unclear whether it may promote resolution of the inflamed colon. In this study, we evaluated the function of Nod2 in myeloid cells in a model of acute colitis and colitis-associated colon cancer (CAC). Methods To ablate Nod2 specifically within the myeloid compartment, we generated LysMCre/+;Nod2fl/fl mice. The role of NOD2 was studied in a setting of Dextran Sodium Sulfate (DSS)-induced colitis and in azoxymethane (AOM)/DSS model. Clinical parameters were quantified by colonoscopy, histological, flow cytometry, and qRT-PCR analysis. Results Upon DSS colitis model, LysMCre/+;Nod2fl/fl mice lost less weight than control littermates and had less severe damage to the colonic epithelium. In the AOM/DSS model, endoscopic monitoring of tumor progression revealed a lowered number of adenomas within the colon of LysMCre/+;Nod2fl/fl mice, associated with less expression of Tgfb. Mechanistically, lysozyme M was required for the improved disease severity in mice with a defect of NOD2 in myeloid cells. Conclusion Our results indicate that loss of Nod2 signaling in myeloid cells aids in the tissue repair of the inflamed large intestine through lysozyme secretion by myeloid cells. These results may pave the way to design new therapeutics to limit the inflammatory and tumorigenic functions of NOD2.
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Affiliation(s)
- Camille Chauvin
- Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France
- Institut national de la santé et de la recherche médicale (INSERM) U1138, Centre de Recherche des Cordeliers, Paris, France
| | - Katarina Radulovic
- Unité de Recherche Clinique, Centre Hospitalier de Valenciennes, Valenciennes, France
| | | | - Myriam Delacre
- Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France
| | - Nadine Waldschmitt
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Paul Régnier
- Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France
- Biotherapy Unit (CIC-BTi), Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | | | | | | | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany
| | - Guillaume Darrasse-Jèze
- Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France
- Université de Paris, Paris Descartes, Faculté de Médecine, Paris, France
- Université Paris Cité, Faculté de Médecine, Paris, France
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26
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Telpaz S, Bel S. Autophagy in intestinal epithelial cells prevents gut inflammation. Trends Cell Biol 2023; 33:817-819. [PMID: 37586983 DOI: 10.1016/j.tcb.2023.07.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 08/18/2023]
Abstract
Intestinal epithelial cells form the largest barrier in the body, separating us from the outside world. Here, we review recent findings that highlight the role of autophagy in the cell-intrinsic response of the epithelial cells to the harsh intestinal environment and how they shape host physiology.
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Affiliation(s)
- Shahar Telpaz
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Shai Bel
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
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27
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Cui C, Wang X, Zheng Y, Li L, Wang F, Wei H, Peng J. Paneth cells protect intestinal stem cell niche to alleviate deoxynivalenol-induced intestinal injury. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 264:115457. [PMID: 37688865 DOI: 10.1016/j.ecoenv.2023.115457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/10/2023] [Accepted: 09/05/2023] [Indexed: 09/11/2023]
Abstract
Deoxynivalenol (DON) is a common toxin in grains and feeds, and DON exposure triggers severe small intestinal injury and inflammation, which harms the health of humans and livestock. DON treatment leads to a decrease in Paneth cells, whereas the role of Paneth cells in DON-induced intestinal injury is poorly understood. We utilized dithizone (40 mg/kg) to keep murine Paneth cell number at a low level. The results showed that dithizone-mediated long-term disruption of Paneth cells aggravated intestinal injury, intestinal stem cell (ISC) loss, and microbiota disorder in DON (2 mg/kg)-treated mice. Unexpectedly, the number of goblet cells and proliferative cells was boosted in mice treated with dithizone and DON. After dithizone and DON treatments, the Firmicutes/Bacteroidetes (F/B) ratio was reduced, and the increased abundance of Dubosiella and the decreased abundance of Lactobacillus were observed in mice. The functional recovery of Paneth cells by lysozyme (200 U/day) supplementation improved intestinal injury and ISC loss in mice after DON challenge. In addition, lysozyme also promoted the growth and ISC activity of intestinal organoids. Taken together, these results demonstrate the protective role of Paneth cells in DON-induced intestinal injury. Our study raises a novel target, Paneth cell, for the treatment of DON exposure.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Xinru Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Yao Zheng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Lindeng Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Fangke Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 400700, China.
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28
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Jordan CKI, Brown RL, Larkinson MLY, Sequeira RP, Edwards AM, Clarke TB. Symbiotic Firmicutes establish mutualism with the host via innate tolerance and resistance to control systemic immunity. Cell Host Microbe 2023; 31:1433-1449.e9. [PMID: 37582375 DOI: 10.1016/j.chom.2023.07.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 08/17/2023]
Abstract
The intestinal microbiota regulates immunity across organ systems. Which symbionts control systemic immunity, the mechanisms they use, and how they avoid widespread inflammatory damage are unclear. We uncover host tolerance and resistance mechanisms that allow Firmicutes from the human microbiota to control systemic immunity without inducing immunopathology. Intestinal processing releases Firmicute glycoconjugates that disseminate, resulting in release of cytokine IL-34 that stimulates macrophages and enhances defenses against pneumonia, sepsis, and meningitis. Despite systemic penetration of Firmicutes, immune homeostasis is maintained through feedback control whereby IL-34-mediated mTORC1 activation in macrophages clears polymeric glycoconjugates from peripheral tissues. Smaller glycoconjugates evading this clearance mechanism are tolerated through sequestration by albumin, which acts as an inflammatory buffer constraining their immunological impact. Without these resistance and tolerance mechanisms, Firmicutes drive catastrophic organ damage and cachexia via IL-1β. This reveals how Firmicutes are safely assimilated into systemic immunity to protect against infection without threatening host viability.
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Affiliation(s)
- Christine K I Jordan
- Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK
| | - Rebecca L Brown
- Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK
| | - Max L Y Larkinson
- Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK
| | - Richard P Sequeira
- Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK
| | - Andrew M Edwards
- Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK
| | - Thomas B Clarke
- Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK.
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29
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Jang KK, Heaney T, London M, Ding Y, Putzel G, Yeung F, Ercelen D, Chen YH, Axelrad J, Gurunathan S, Zhou C, Podkowik M, Arguelles N, Srivastava A, Shopsin B, Torres VJ, Keestra-Gounder AM, Pironti A, Griffin ME, Hang HC, Cadwell K. Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization. Cell Host Microbe 2023; 31:1450-1468.e8. [PMID: 37652008 PMCID: PMC10502928 DOI: 10.1016/j.chom.2023.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 07/02/2023] [Accepted: 08/07/2023] [Indexed: 09/02/2023]
Abstract
Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1β (IL-1β) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
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Affiliation(s)
- Kyung Ku Jang
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Thomas Heaney
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Mariya London
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Yi Ding
- Department of Laboratory Medicine, Geisinger Health, Danville, PA 17822, USA
| | - Gregory Putzel
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Frank Yeung
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Defne Ercelen
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ying-Han Chen
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Jordan Axelrad
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Sakteesh Gurunathan
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Chaoting Zhou
- Cell and Molecular Biology Graduate Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Magdalena Podkowik
- Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA; Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Natalia Arguelles
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Anusha Srivastava
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Bo Shopsin
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA; Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Victor J Torres
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - A Marijke Keestra-Gounder
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Alejandro Pironti
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Matthew E Griffin
- Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Howard C Hang
- Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Ken Cadwell
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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Richard N, Savoye G, Leboutte M, Amamou A, Ghosh S, Marion-Letellier R. Crohn’s disease: Why the ileum? World J Gastroenterol 2023; 29:3222-3240. [PMID: 37377591 PMCID: PMC10292140 DOI: 10.3748/wjg.v29.i21.3222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
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Affiliation(s)
- Nicolas Richard
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Guillaume Savoye
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Mathilde Leboutte
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Asma Amamou
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Rachel Marion-Letellier
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
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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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32
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Boccuto L, Tack J, Ianiro G, Abenavoli L, Scarpellini E. Human Genes Involved in the Interaction between Host and Gut Microbiome: Regulation and Pathogenic Mechanisms. Genes (Basel) 2023; 14:genes14040857. [PMID: 37107615 PMCID: PMC10137629 DOI: 10.3390/genes14040857] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/24/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Introduction: The umbrella term “human gut microbiota” describes the complex ecosystem harboring our gut. It includes bacteria, viruses, protozoa, archaea, fungi, and yeasts. This taxonomic classification does not describe its functions, which encompass nutrients digestion and absorption, immune system regulation, and host metabolism. “Gut microbiome” indicates instead the genome belonging to these “microbes” actively involved in these functions. However, the interaction between the host genome and the microbial ones determines the fine functioning of our organism. Methods: We reviewed the data available in the scientific literature on the definition of gut microbiota, gut microbiome, and the data on human genes involved in the interaction with the latter. We consulted the main medical databases using the following keywords, acronyms, and their associations: gut microbiota, gut microbiome, human genes, immune function, and metabolism. Results: Candidate human genes encoding enzymes, inflammatory cytokines, and proteins show similarity with those included in the gut microbiome. These findings have become available through newer artificial intelligence (AI) algorithms allowing big data analysis. From an evolutionary point of view, these pieces of evidence explain the strict and sophisticated interaction at the basis of human metabolism and immunity regulation in humans. They unravel more and more physiopathologic pathways included in human health and disease. Discussion: Several lines of evidence also obtained through big data analysis support the bi-directional role of gut microbiome and human genome in host metabolism and immune system regulation.
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Affiliation(s)
- Luigi Boccuto
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson University School of Health Research, Clemson, SC 29631, USA
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium
| | - Gianluca Ianiro
- Department of Medical and Surgical Sciences, Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Emidio Scarpellini
- Translational Research Center for Gastrointestinal Disorders (T.A.R.G.I.D.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Lueven, Belgium
- Clinical Nutrition and Hepatology Unit, San Benedetto del Tronto General Hospital, 63074 San Benedetto del Tronto, Italy
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Dallmann-Sauer M, Xu YZ, da Costa ALF, Tao S, Gomes TA, Prata RBDS, Correa-Macedo W, Manry J, Alcaïs A, Abel L, Cobat A, Fava VM, Pinheiro RO, Lara FA, Probst CM, Mira MT, Schurr E. Allele-dependent interaction of LRRK2 and NOD2 in leprosy. PLoS Pathog 2023; 19:e1011260. [PMID: 36972292 PMCID: PMC10079233 DOI: 10.1371/journal.ppat.1011260] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 04/06/2023] [Accepted: 03/02/2023] [Indexed: 03/29/2023] Open
Abstract
Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn’s disease and Parkinson’s disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.
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Affiliation(s)
- Monica Dallmann-Sauer
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre; Montreal, Canada
- McGill International TB Centre, McGill University; Montreal, Canada
- Departments of Human Genetics and Medicine, Faculty of Medicine and Health Science, McGill University; Montreal, Canada
- Graduate Program in Health Sciences, School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná; Curitiba, Brazil
| | - Yong Zhong Xu
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre; Montreal, Canada
- McGill International TB Centre, McGill University; Montreal, Canada
| | - Ana Lúcia França da Costa
- Department of Specialized Medicine, Health Sciences Center, Federal University of Piauí; Teresina, Brazil
| | - Shao Tao
- Division of Experimental Medicine, Faculty of Medicine, McGill University; Montreal, Canada
- The Translational Research in Respiratory Diseases Program, The Research Institute of the McGill University Health Centre; Montreal, Canada
| | - Tiago Araujo Gomes
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation; Rio de Janeiro, Brazil
| | | | - Wilian Correa-Macedo
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre; Montreal, Canada
- McGill International TB Centre, McGill University; Montreal, Canada
- Department of Biochemistry, Faculty of Medicine and Health Science, McGill University; Montreal, Canada
| | - Jérémy Manry
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre; Montreal, Canada
- McGill International TB Centre, McGill University; Montreal, Canada
| | - Alexandre Alcaïs
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U.1163, Paris, France
- Université Paris Cité, Imagine Institute, Paris, France
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U.1163, Paris, France
- Université Paris Cité, Imagine Institute, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, United States of America
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U.1163, Paris, France
- Université Paris Cité, Imagine Institute, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, United States of America
| | - Vinicius M. Fava
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre; Montreal, Canada
- McGill International TB Centre, McGill University; Montreal, Canada
| | - Roberta Olmo Pinheiro
- Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation; Rio de Janeiro, Brazil
| | - Flavio Alves Lara
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation; Rio de Janeiro, Brazil
| | - Christian M. Probst
- Laboratory of Systems and Molecular Biology of Trypanosomatids, Instituto Carlos Chagas; FIOCRUZ, Curitiba, Brazil
| | - Marcelo T. Mira
- Graduate Program in Health Sciences, School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná; Curitiba, Brazil
- * E-mail: (M.T.M); (E.S.)
| | - Erwin Schurr
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre; Montreal, Canada
- McGill International TB Centre, McGill University; Montreal, Canada
- Departments of Human Genetics and Medicine, Faculty of Medicine and Health Science, McGill University; Montreal, Canada
- Department of Biochemistry, Faculty of Medicine and Health Science, McGill University; Montreal, Canada
- * E-mail: (M.T.M); (E.S.)
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Cui C, Wang F, Zheng Y, Wei H, Peng J. From birth to death: The hardworking life of Paneth cell in the small intestine. Front Immunol 2023; 14:1122258. [PMID: 36969191 PMCID: PMC10036411 DOI: 10.3389/fimmu.2023.1122258] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/28/2023] [Indexed: 03/12/2023] Open
Abstract
Paneth cells are a group of unique intestinal epithelial cells, and they play an important role in host-microbiota interactions. At the origin of Paneth cell life, several pathways such as Wnt, Notch, and BMP signaling, affect the differentiation of Paneth cells. After lineage commitment, Paneth cells migrate downward and reside in the base of crypts, and they possess abundant granules in their apical cytoplasm. These granules contain some important substances such as antimicrobial peptides and growth factors. Antimicrobial peptides can regulate the composition of microbiota and defend against mucosal penetration by commensal and pathogenic bacteria to protect the intestinal epithelia. The growth factors derived from Paneth cells contribute to the maintenance of the normal functions of intestinal stem cells. The presence of Paneth cells ensures the sterile environment and clearance of apoptotic cells from crypts to maintain the intestinal homeostasis. At the end of their lives, Paneth cells experience different types of programmed cell death such as apoptosis and necroptosis. During intestinal injury, Paneth cells can acquire stem cell features to restore the intestinal epithelial integrity. In view of the crucial roles of Paneth cells in the intestinal homeostasis, research on Paneth cells has rapidly developed in recent years, and the existing reviews on Paneth cells have mainly focused on their functions of antimicrobial peptide secretion and intestinal stem cell support. This review aims to summarize the approaches to studying Paneth cells and introduce the whole life experience of Paneth cells from birth to death.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Fangke Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Yao Zheng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- *Correspondence: Jian Peng,
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Khan MA, Haider N, Singh T, Bandopadhyay R, Ghoneim MM, Alshehri S, Taha M, Ahmad J, Mishra A. Promising biomarkers and therapeutic targets for the management of Parkinson's disease: recent advancements and contemporary research. Metab Brain Dis 2023; 38:873-919. [PMID: 36807081 DOI: 10.1007/s11011-023-01180-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 02/04/2023] [Indexed: 02/23/2023]
Abstract
Parkinson's disease (PD) is one of the progressive neurological diseases which affect around 10 million population worldwide. The clinical manifestation of motor symptoms in PD patients appears later when most dopaminergic neurons have degenerated. Thus, for better management of PD, the development of accurate biomarkers for the early prognosis of PD is imperative. The present work will discuss the potential biomarkers from various attributes covering biochemical, microRNA, and neuroimaging aspects (α-synuclein, DJ-1, UCH-L1, β-glucocerebrosidase, BDNF, etc.) for diagnosis, recent development in PD management, and major limitations with current and conventional anti-Parkinson therapy. This manuscript summarizes potential biomarkers and therapeutic targets, based on available preclinical and clinical evidence, for better management of PD.
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Affiliation(s)
- Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Nafis Haider
- Prince Sultan Military College of Health Sciences, Dhahran, 34313, Saudi Arabia
| | - Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, 77807, USA
| | - Ritam Bandopadhyay
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India
| | - Mohammed M Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, 13713, Saudi Arabia
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Murtada Taha
- Prince Sultan Military College of Health Sciences, Dhahran, 34313, Saudi Arabia
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, 11001, Saudi Arabia
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) - Guwahati, Sila Katamur (Halugurisuk), Kamrup, Changsari, Assam, 781101, India.
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Jang KK, Heaney T, London M, Ding Y, Yeung F, Ercelen D, Chen YH, Axelrad J, Gurunathan S, Marijke Keestra-Gounder A, Griffin ME, Hang HC, Cadwell K. Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.29.526128. [PMID: 36778381 PMCID: PMC9915521 DOI: 10.1101/2023.01.29.526128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium ( Efm ) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA. Microbiota sensing by NOD2 in myeloid cells mediated IL-1β secretion and increased the proportion of IL-22-producing CD4 + T helper cells and innate lymphoid cells. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
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37
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Peter I, Strober W. Immunological Features of LRRK2 Function and Its Role in the Gut-Brain Axis Governing Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2023; 13:279-296. [PMID: 37066923 PMCID: PMC10200211 DOI: 10.3233/jpd-230021] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 04/18/2023]
Abstract
Emerging evidence implicates intestinal involvement in the onset and/or progression on the selective degeneration of dopaminergic neurons characterizing Parkinson's disease (PD). On the one hand, there are studies supporting the Braak hypothesis that holds that pathologic α-synuclein, a hallmark of PD, is secreted by enteric nerves into intestinal tissue and finds its way to the central nervous system (CNS) via retrograde movement in the vagus nerve. On the other hand, there is data showing that cells bearing leucine-rich repeat kinase 2 (LRRK2), a signaling molecule with genetic variants associated with both PD and with inflammatory bowel disease, can be activated in intestinal tissue and contribute locally to intestinal inflammation, or peripherally to PD pathogenesis via cell trafficking to the CNS. Importantly, these gut-centered factors affecting PD development are not necessarily independent of one another: they may interact and enhance their respective pathologic functions. In this review, we discuss this possibility by analysis of studies conducted in recent years focusing on the ability of LRRK2 to shape immunologic responses and the role of α-synuclein in influencing this ability.
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Affiliation(s)
- Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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38
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Zhou YD, Liang FX, Tian HR, Luo D, Wang YY, Yang SR. Mechanisms of gut microbiota-immune-host interaction on glucose regulation in type 2 diabetes. Front Microbiol 2023; 14:1121695. [PMID: 36891383 PMCID: PMC9986296 DOI: 10.3389/fmicb.2023.1121695] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/31/2023] [Indexed: 02/22/2023] Open
Abstract
Intestinal absorption of food is one of the sources of glucose. Insulin resistance and impaired glucose tolerance caused by lifestyle and diet are the precursors of type 2 diabetes. Patients with type 2 diabetes have trouble controlling their blood sugar levels. For long-term health, strict glycemic management is necessary. Although it is thought to be well correlated with metabolic diseases like obesity, insulin resistance, and diabetes, its molecular mechanism is still not completely understood. Disturbed microbiota triggers the gut immune response to reshape the gut homeostasis. This interaction not only maintains the dynamic changes of intestinal flora, but also preserves the integrity of the intestinal barrier. Meanwhile, the microbiota establishes a systemic multiorgan dialog on the gut-brain and gut-liver axes, intestinal absorption of a high-fat diet affects the host's feeding preference and systemic metabolism. Intervention in the gut microbiota can combat the decreased glucose tolerance and insulin sensitivity linked to metabolic diseases both centrally and peripherally. Moreover, the pharmacokinetics of oral hypoglycemic medications are also influenced by gut microbiota. The accumulation of drugs in the gut microbiota not only affects the drug efficacy, but also changes the composition and function of them, thus may help to explain individual therapeutic variances in pharmacological efficacy. Regulating gut microbiota through healthy dietary patterns or supplementing pro/prebiotics can provide guidance for lifestyle interventions in people with poor glycemic control. Traditional Chinese medicine can also be used as complementary medicine to effectively regulate intestinal homeostasis. Intestinal microbiota is becoming a new target against metabolic diseases, so more evidence is needed to elucidate the intricate microbiota-immune-host relationship, and explore the therapeutic potential of targeting intestinal microbiota.
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Affiliation(s)
- Yu-Dian Zhou
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Feng-Xia Liang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Hao-Ran Tian
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Dan Luo
- Department of Respiratory Wuhan No.1 Hospital, Wuhan, Hebei, China
| | - Ya-Yuan Wang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Shu-Rui Yang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
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39
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Wallaeys C, Garcia‐Gonzalez N, Libert C. Paneth cells as the cornerstones of intestinal and organismal health: a primer. EMBO Mol Med 2022; 15:e16427. [PMID: 36573340 PMCID: PMC9906427 DOI: 10.15252/emmm.202216427] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/24/2022] [Accepted: 09/29/2022] [Indexed: 12/28/2022] Open
Abstract
Paneth cells are versatile secretory cells located in the crypts of Lieberkühn of the small intestine. In normal conditions, they function as the cornerstones of intestinal health by preserving homeostasis. They perform this function by providing niche factors to the intestinal stem cell compartment, regulating the composition of the microbiome through the production and secretion of antimicrobial peptides, performing phagocytosis and efferocytosis, taking up heavy metals, and preserving barrier integrity. Disturbances in one or more of these functions can lead to intestinal as well as systemic inflammatory and infectious diseases. This review discusses the multiple functions of Paneth cells, and the mechanisms and consequences of Paneth cell dysfunction. It also provides an overview of the tools available for studying Paneth cells.
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Affiliation(s)
- Charlotte Wallaeys
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Natalia Garcia‐Gonzalez
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Claude Libert
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
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Genetic and Epigenetic Etiology of Inflammatory Bowel Disease: An Update. Genes (Basel) 2022; 13:genes13122388. [PMID: 36553655 PMCID: PMC9778199 DOI: 10.3390/genes13122388] [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: 11/17/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease with periods of exacerbation and remission of the disease. The etiology of IBD is not fully understood. Many studies point to the presence of genetic, immunological, environmental, and microbiological factors and the interactions between them in the occurrence of IBD. The review looks at genetic factors in the context of both IBD predisposition and pharmacogenetics.
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41
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Li P, Gao M, Fu J, Zhao Y, Liu Y, Yan S, Lv Z, Guo Y. Construction of low intestinal bacteria model and its effect on laying performance and immune function of laying hens. Poult Sci 2022; 102:102327. [PMID: 36812879 PMCID: PMC9975688 DOI: 10.1016/j.psj.2022.102327] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/04/2022] [Accepted: 11/05/2022] [Indexed: 11/12/2022] Open
Abstract
The objective of this study was to establish a low-bacteria intestinal model in chickens, and then to investigate the characteristics involving in immune function and intestinal environment of this model. A total of 180 twenty-one-week-old Hy-line gray layers were randomly allocated into 2 treatment groups. Hens were fed with a basic diet (Control), or an antibiotic combination diet (ABS) for 5 weeks. Results showed that the total bacteria in the ileal chyme were significantly dropped after ABS treatment. Compared with the Control group, the genus-level bacteria such as Romboutsia, Enterococcus, and Aeriscardovia were reduced in the ileal chyme of the ABS group (P < 0.05). In addition, the relative abundance of Lactobacillus_delbrueckii, Lactobacillus_aviarius, Lactobacillus_gasseri, and Lactobacillus_agilis in the ileal chyme were also descended (P < 0.05). However, Lactobacillus_coleohominis, Lactobacillus_salivarius, and Lolium_perenne were elevated in the ABS group (P < 0.05). Beyond that, ABS treatment decreased the levels of interleukin-10 (IL-10) and β-defensin 1 in the serum, as well as the number of goblet cells in the ileal villi (P < 0.05). Additionally, the genes mRNA levels of the ileum such as Mucin2, Toll-like receptors 4 (TLR4), Myeloid differentiation factor 88 (MYD88), NF-κB, IL-1β, Interferon-gama (IFN-γ), IL-4 and the ratio of IFN-γ to IL-4 were also down-regulated in the ABS group (P < 0.05). In addition, there were no significant changes about egg production rate and egg quality in the ABS group. In conclusion, dietary supplemental antibiotic combination for 5 weeks could establish a low intestinal bacteria model of hens. The establishment of a low intestinal bacteria model did not affect the egg-laying performance, while caused immune suppression in laying hens.
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Affiliation(s)
- Peng Li
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China,Engineering Research Center of Feed Protein Resources on Agricultural By-products, Ministry of Education, Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei 430023, China
| | - Mingkun Gao
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| | - Jiahuan Fu
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| | - Yizhu Zhao
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| | - Yongfa Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| | - Shaojia Yan
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| | - Zengpeng Lv
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| | - Yuming Guo
- State Key Laboratory of Animal Nutrition, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China.
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42
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Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol 2022; 22:657-673. [PMID: 35246670 PMCID: PMC8895080 DOI: 10.1038/s41577-022-00684-6] [Citation(s) in RCA: 644] [Impact Index Per Article: 214.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2022] [Indexed: 01/18/2023]
Abstract
Parkinson disease (PD) is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system and involves a fundamental role of neuroinflammation in its pathophysiology. Neurohistological and neuroimaging studies support the presence of ongoing and end-stage neuroinflammatory processes in PD. Moreover, numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest alterations in markers of inflammation and immune cell populations that could initiate or exacerbate neuroinflammation and perpetuate the neurodegenerative process. A number of disease genes and risk factors have been identified as modulators of immune function in PD and evidence is mounting for a role of viral or bacterial exposure, pesticides and alterations in gut microbiota in disease pathogenesis. This has led to the hypothesis that complex gene-by-environment interactions combine with an ageing immune system to create the 'perfect storm' that enables the development and progression of PD. We discuss the evidence for this hypothesis and opportunities to harness the emerging immunological knowledge from patients with PD to create better preclinical models with the long-term goal of enabling earlier identification of at-risk individuals to prevent, delay and more effectively treat the disease.
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Affiliation(s)
- Malú Gámez Tansey
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA.
| | - Rebecca L Wallings
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA
| | - Madelyn C Houser
- Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA, USA
| | - Mary K Herrick
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA
| | - Cody E Keating
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA
| | - Valerie Joers
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA
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43
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Chen SJ, Lin CH. Gut microenvironmental changes as a potential trigger in Parkinson's disease through the gut-brain axis. J Biomed Sci 2022; 29:54. [PMID: 35897024 PMCID: PMC9327249 DOI: 10.1186/s12929-022-00839-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/22/2022] [Indexed: 11/10/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease attributed to the synergistic effects of genetic risk and environmental stimuli. Although PD is characterized by motor dysfunction resulting from intraneuronal alpha-synuclein accumulations, termed Lewy bodies, and dopaminergic neuronal degeneration in the substantia nigra, multiple systems are involved in the disease process, resulting in heterogenous clinical presentation and progression. Genetic predisposition to PD regarding aberrant immune responses, abnormal protein aggregation, autophagolysosomal impairment, and mitochondrial dysfunction leads to vulnerable neurons that are sensitive to environmental triggers and, together, result in neuronal degeneration. Neuropathology studies have shown that, at least in some patients, Lewy bodies start from the enteric nervous system and then spread to the central dopaminergic neurons through the gut-brain axis, suggesting the contribution of an altered gut microenvironment in the pathogenesis of PD. A plethora of evidence has revealed different gut microbiomes and gut metabolites in patients with PD compared to unaffected controls. Chronic gut inflammation and impaired intestinal barrier integrity have been observed in human PD patients and mouse models of PD. These observations led to the hypothesis that an altered gut microenvironment is a potential trigger of the PD process in a genetically susceptible host. In this review, we will discuss the complex interplay between genetic factors and gut microenvironmental changes contributing to PD pathogenesis.
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Affiliation(s)
- Szu-Ju Chen
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.,Department of Neurology, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. .,Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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44
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Berberine Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis and Inhibits the Secretion of Gut Lysozyme via Promoting Autophagy. Metabolites 2022; 12:metabo12080676. [PMID: 35893243 PMCID: PMC9394306 DOI: 10.3390/metabo12080676] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
Abstract
Ulcerative colitis (UC) is one of the primary types of inflammatory bowel disease, the occurrence of which has been increasing worldwide. Research in recent years has found that the level of lysozyme in the feces and blood of UC patients is abnormally elevated, and the bacterial product after the action of lysozyme can be used as an agonist to recognize different cell pattern receptors, thus regulating the process of intestinal inflammation. Berberine (BBR), as a clinical anti-diarrhea and anti-inflammatory drug, has been used in China for hundreds of years. In this study, results showed that BBR can significantly inhibit the expression and secretion of lysozyme in mice. Therefore, we try to investigate the mechanism behind it and elucidate the new anti-inflammatory mechanism of BBR. In vitro, lipopolysaccharide (LPS) was used to establish an inflammatory cell model, and transcriptomic was used to analyze the differentially expressed genes (DEGs) between the LPS group and the LPS + BBR treatment group. In vivo, dextran sulfate sodium salt (DSS) was used to establish a UC mice model, and histologic section and immunofluorescence trails were used to estimate the effect of BBR on UC mice and the expression of lysozyme in Paneth cells. Research results showed that BBR can inhibit the expression and secretion of lysozyme by promoting autophagy via the AMPK/MTOR/ULK1 pathway, and BBR promotes the maturation and expression of lysosomes. Accordingly, we conclude that inhibiting the expression and secretion of intestinal lysozyme is a new anti-inflammatory mechanism of BBR.
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45
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Tsafaras G, Baekelandt V. The role of LRRK2 in the periphery: link with Parkinson's disease and inflammatory diseases. Neurobiol Dis 2022; 172:105806. [PMID: 35781002 DOI: 10.1016/j.nbd.2022.105806] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/30/2022] [Accepted: 06/22/2022] [Indexed: 02/07/2023] Open
Abstract
Parkinson's disease (PD) is currently considered a multisystemic disorder rather than a pure brain disease, in line with the multiple hit hypothesis from Braak. However, despite increasing evidence that the pathology might originate in the periphery, multiple unknown aspects and contradictory data on the pathological processes taking place in the periphery jeopardize the interpretation and therapeutic targeting of PD. Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been widely linked with familial and sporadic PD cases. However, the actual role of LRRK2 in PD pathophysiology is far from understood. There is evidence that LRRK2 may be involved in alpha-synuclein (α-synuclein) pathology and immune cell regulation, but it has also been associated with inflammatory diseases such as inflammatory bowel disease, tuberculosis, leprosy, and several other bacterial infections. In this review, we focus on the different roles of LRRK2 in the periphery. More specifically, we discuss the involvement of LRRK2 in the propagation of α-synuclein pathology and its regulatory role in peripheral inflammation. A deeper understanding of the multidimensional functions of LRRK2 will pave the way for more accurate characterization of PD pathophysiology and its association with other inflammatory diseases.
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Affiliation(s)
- George Tsafaras
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
| | - Veerle Baekelandt
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
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46
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Trinh J, Schymanski EL, Smajic S, Kasten M, Sammler E, Grünewald A. Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease. MED GENET-BERLIN 2022; 34:103-116. [PMID: 38835904 PMCID: PMC11006382 DOI: 10.1515/medgen-2022-2127] [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] [Indexed: 06/06/2024]
Abstract
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson's disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2's involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.
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Affiliation(s)
- Joanne Trinh
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Emma L. Schymanski
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Semra Smajic
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Meike Kasten
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
- Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
| | - Esther Sammler
- Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
- Department of Neurology, School of Medicine, Dundee, Ninewells Hospital, Dundee, UK
| | - Anne Grünewald
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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Abstract
We demonstrate that AP patients and experimental AP mice exhibited a dysfunction of Paneth cells. Our
in vivo
research showed that the severity of AP was exacerbated by the long-term dysfunction of Paneth cells, which was associated with gut microbiota disorder.
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48
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Effect of LRRK2 protein and activity on stimulated cytokines in human monocytes and macrophages. NPJ Parkinsons Dis 2022; 8:34. [PMID: 35347144 PMCID: PMC8960803 DOI: 10.1038/s41531-022-00297-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 02/17/2022] [Indexed: 12/20/2022] Open
Abstract
Leucine-rich-repeat kinase 2 (LRRK2), a potential therapeutic target for the treatment of Parkinson's disease (PD), is highly expressed in monocytes and macrophages and may play a role in the regulation of inflammatory pathways. To determine how LRRK2 protein levels and/or its activity modulate inflammatory cytokine/chemokine levels in human immune cells, isogenic human induced pluripotent stem cells (iPSC) with the LRRK2-activating G2019S mutation, wild-type LRRK2, and iPSC deficient in LRRK2 were differentiated to monocytes and macrophages and stimulated with inflammatory toll-like receptor (TLR) agonists in the presence and absence of LRRK2 kinase inhibitors. The effect of LRRK2 inhibitors and the effect of increasing LRRK2 levels with interferon gamma on TLR-stimulated cytokines were also assessed in primary peripheral blood-derived monocytes. Monocytes and macrophages with the LRRK2 G2019S mutation had significantly higher levels of cytokines and chemokines in tissue culture media following stimulation with TLR agonists compared to isogenic controls. Knockout of LRRK2 impaired phagocytosis but did not significantly affect TLR-mediated cytokine levels. Interferon gamma significantly increased the levels of LRRK2 and phosphorylation of its downstream Rab10 substrate, and potentiated TLR-mediated cytokine levels. LRRK2 kinase inhibitors did not have a major effect on TLR-stimulated cytokine levels. Results suggest that the LRRK2 G2019S mutation may potentiate inflammation following activation of TLRs. However, this was not dependent on LRRK2 kinase activity. Indeed, LRRK2 kinase inhibitors had little effect on TLR-mediated inflammation under the conditions employed in this study.
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49
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Li W, Hao CJ, Hao ZH, Ma J, Wang QC, Yuan YF, Gong JJ, Chen YY, Yu JY, Wei AH. New insights into the pathogenesis of Hermansky-Pudlak syndrome. Pigment Cell Melanoma Res 2022; 35:290-302. [PMID: 35129281 DOI: 10.1111/pcmr.13030] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 12/14/2022]
Abstract
Hermansky-Pudlak syndrome (HPS) is characterized by defects of multiple tissue-specific lysosome-related organelles (LROs), typically manifesting with oculocutaneous albinism or ocular albinism, bleeding tendency, and in some cases with pulmonary fibrosis, inflammatory bowel disease or immunodeficiency, neuropsychological disorders. Eleven HPS subtypes in humans and at least 15 subtypes in mice have been molecularly identified. Current understanding of the underlying mechanisms of HPS is focusing on the defective biogenesis of LROs. Compelling evidences have shown that HPS protein-associated complexes (HPACs) function in cargo transport, cargo recycling, and cargo removal to maintain LRO homeostasis. Further investigation on the molecular and cellular mechanism of LRO biogenesis and secretion will be helpful for better understanding of its pathogenesis and for the precise intervention of HPS.
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Affiliation(s)
- Wei Li
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Chan-Juan Hao
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Zhen-Hua Hao
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Jing Ma
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Qiao-Chu Wang
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Ye-Feng Yuan
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Juan-Juan Gong
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Yuan-Ying Chen
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Jia-Ying Yu
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing, China.,MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China
| | - Ai-Hua Wei
- Department of Dermatology, Tongren Hospital, Capital Medical University, Beijing, China
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50
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Gouda NA, Elkamhawy A, Cho J. Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update. Biomedicines 2022; 10:biomedicines10020371. [PMID: 35203580 PMCID: PMC8962417 DOI: 10.3390/biomedicines10020371] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 11/16/2022] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis.
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Affiliation(s)
- Noha A. Gouda
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Korea; (N.A.G.); (A.E.)
| | - Ahmed Elkamhawy
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Korea; (N.A.G.); (A.E.)
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Jungsook Cho
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Korea; (N.A.G.); (A.E.)
- Correspondence:
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