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Zhang J, Jiang Y, Fan D, Qiu Z, He X, Liu S, Li L, Dai Z, Zhang L, Shu Z, Li L, Zhang H, Yang T, Luo Y. Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4 + T cell for inflammatory bowel diseases treatment. Cell Rep Med 2024; 5:101840. [PMID: 39626672 PMCID: PMC11722089 DOI: 10.1016/j.xcrm.2024.101840] [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: 04/23/2024] [Revised: 09/25/2024] [Accepted: 11/05/2024] [Indexed: 12/20/2024]
Abstract
Inflammatory bowel disease (IBD) is an autoimmune disorder, and despite the availability of multiple Food and Drug Administration (FDA)-approved therapies, current clinical needs remain unmet. In this study, we find that caseinolytic protease P (ClpP) expression is markedly upregulated in colonic tissues from IBD patients and preclinical colitis models, particularly in CD4+ T cells. Subsequently, a small molecule, namely NCA029, is identified, and its therapeutic efficacy and mechanism of action are investigated both in vitro and in vivo. Oral administration of NCA029 significantly alleviates symptoms associated with dextran sulfate sodium (DSS)-induced acute and interleukin (IL)-10-deficient chronic colitis. The effects of NCA029 are largely dependent on its selective binding to ClpP in CD4+ T cells, thereby mitigating inflammation and restoring intestinal barrier function. Furthermore, NCA029 activates ClpP to promote oxidative phosphorylation (OXPHOS) inhibition and concomitantly modulate the Th17/Treg balance. In conclusion, our study develops a therapeutic strategy for treating IBD through the chemical activation of ClpP.
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Affiliation(s)
- Jiangnan Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yunhan Jiang
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dongmei Fan
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhiqiang Qiu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinlian He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Song Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Linjie Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhengyi Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lidan Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ziyi Shu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China; Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China; Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Youfu Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
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Li B, Zhang Y, Huang N, Wang J, Zhang X, Meng Q, Wang J, Wang C, Li X, Chen R, Zhang L. DNA hypomethylation of Th17 cells by ambient particulate pollutants enhances neutrophil recruitment in murine models of allergic airway inflammation. Allergy 2024. [PMID: 39508385 DOI: 10.1111/all.16389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/16/2024] [Accepted: 10/23/2024] [Indexed: 11/15/2024]
Affiliation(s)
- Bin Li
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
| | - Yuan Zhang
- Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, P. R. China
- Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing, P. R. China
| | - Nannan Huang
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
| | - Jing Wang
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
| | - Xianan Zhang
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
| | - Qingtao Meng
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
- Laboratory for Environmental Health and Allergic Nasal Diseases, Laboratory for Clinical Medicine, Capital Medical University, Beijing, P. R. China
| | - Jiajia Wang
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
- Laboratory for Environmental Health and Allergic Nasal Diseases, Laboratory for Clinical Medicine, Capital Medical University, Beijing, P. R. China
| | - Chengshuo Wang
- Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, P. R. China
- Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing, P. R. China
| | - Xiaobo Li
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
- Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing, P. R. China
- Laboratory for Environmental Health and Allergic Nasal Diseases, Laboratory for Clinical Medicine, Capital Medical University, Beijing, P. R. China
| | - Rui Chen
- School of Public Health, Capital Medical University, Beijing, People's Republic of China
- Laboratory for Environmental Health and Allergic Nasal Diseases, Laboratory for Clinical Medicine, Capital Medical University, Beijing, P. R. China
- Department of Occupational and Environmental Health, Fourth Military Medical University, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an, P. R. China
| | - Luo Zhang
- Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, P. R. China
- Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing, P. R. China
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Estarreja J, Caldeira G, Silva I, Mendes P, Mateus V. The Pharmacological Effect of Hemin in Inflammatory-Related Diseases: A Systematic Review. Biomedicines 2024; 12:898. [PMID: 38672251 PMCID: PMC11048114 DOI: 10.3390/biomedicines12040898] [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: 03/07/2024] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Hemin is clinically used in acute attacks of porphyria; however, recent evidence has also highlighted its capability to stimulate the heme oxygenase enzyme, being associated with cytoprotective, antioxidant, and anti-inflammatory effects. Indeed, current preclinical evidence emphasizes the potential anti-inflammatory role of hemin through its use in animal models of disease. Nevertheless, there is no consensus about the underlying mechanism(s) and the most optimal therapeutic regimens. Therefore, this review aims to summarize, analyze, and discuss the current preclinical evidence concerning the pharmacological effect of hemin. METHODS Following the application of the search expression and the retrieval of the articles, only nonclinical studies in vivo written in English were considered, where the potential anti-inflammatory effect of hemin was evaluated. RESULTS Forty-nine articles were included according to the eligibility criteria established. The results obtained show the preference of using 30 to 50 mg/kg of hemin, administered intraperitoneally, in both acute and chronic contexts. This drug demonstrates significant anti-inflammatory and antioxidant activities considering its capacity for reducing the expression of proinflammatory and oxidative markers. CONCLUSIONS This review highlighted the significant anti-inflammatory and antioxidant effects of hemin, providing a clearer vision for the medical community about the use of this drug in several human diseases.
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Affiliation(s)
- João Estarreja
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
| | - Gonçalo Caldeira
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
| | - Inês Silva
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal
| | - Priscila Mendes
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
| | - Vanessa Mateus
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal
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Wang Y, Yang C, Hou Y, Wang J, Zhang K, Wang L, Sun D, Li X, Wei R, Nian H. Dimethyl itaconate inhibits antigen-specific Th17 cell responses and autoimmune inflammation via modulating NRF2/STAT3 signaling. FASEB J 2024; 38:e23607. [PMID: 38581245 DOI: 10.1096/fj.202302293rr] [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: 11/09/2023] [Revised: 03/14/2024] [Accepted: 03/29/2024] [Indexed: 04/08/2024]
Abstract
Pathogenic Th17 cells play a crucial role in autoimmune diseases like uveitis and its animal model, experimental autoimmune uveitis (EAU). Dimethyl itaconate (DMI) possesses potent anti-inflammatory effects. However, there is still a lack of knowledge about the role of DMI in regulating pathogenic Th17 cells and EAU. Here, we reported that intraperitoneal administration of DMI significantly inhibited the severity of EAU via selectively suppressing Th17 cell responses. In vitro antigen stimulation studies revealed that DMI dramatically decreased the frequencies and function of antigen-specific Th17, but not Th1, cells. Moreover, DMI hampered the differentiation of naive CD4+ T cells toward pathogenic Th17 cells. DMI-treated DCs produced less IL-1β, IL-6, and IL-23, and displayed an impaired ability to stimulate antigen-specific Th17 activation. Mechanistically, DMI activated the NRF2/HO-1 pathway and suppressed STAT3 signaling, which subsequently restrains p-STAT3 nuclear translocation, leading to decreased pathogenic Th17 cell responses. Thus, we have identified an important role for DMI in regulating pathogenic Th17 cells, supporting DMI as a promising therapy in Th17 cell-driven autoimmune diseases including uveitis.
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Affiliation(s)
- Ying Wang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Chao Yang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Yubiao Hou
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Jiali Wang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Kailang Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Lihua Wang
- Department of Kidney Diseases and Blood Purification, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Deming Sun
- Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, USA
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Ruihua Wei
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Hong Nian
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
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Sumi M, Westcott R, Stuehr E, Ghosh C, Stuehr DJ, Ghosh A. Regional variations in allergen-induced airway inflammation correspond to changes in soluble guanylyl cyclase heme and expression of heme oxygenase-1. FASEB J 2024; 38:e23572. [PMID: 38512139 PMCID: PMC10977653 DOI: 10.1096/fj.202301626rrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 02/09/2024] [Accepted: 03/08/2024] [Indexed: 03/22/2024]
Abstract
Asthma is characterized by airway remodeling and hyperreactivity. Our earlier studies determined that the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cGMP pathway plays a significant role in human lung bronchodilation. However, this bronchodilation is dysfunctional in asthma due to high NO levels, which cause sGC to become heme-free and desensitized to its natural activator, NO. In order to determine how asthma impacts the various lung segments/lobes, we mapped the inflammatory regions of lungs to determine whether such regions coincided with molecular signatures of sGC dysfunction. We demonstrate using murine models of asthma (OVA and CFA/HDM) that the inflamed segments of these murine lungs can be tracked by upregulated expression of HO1 and these regions in turn overlap with regions of heme-free sGC as evidenced by a decreased sGC-α1β1 heterodimer and an increased response to heme-independent sGC activator, BAY 60-2770, relative to naïve uninflamed regions. We also find that NO generated from iNOS upregulation in the inflamed segments has a higher impact on developing heme-free sGC as increasing iNOS activity correlates linearly with elevated heme-independent sGC activation. This excess NO works by affecting the epithelial lung hemoglobin (Hb) to become heme-free in asthma, thereby causing the Hb to lose its NO scavenging function and exposing the underlying smooth muscle sGC to excess NO, which in turn becomes heme-free. Recognition of these specific lung segments enhances our understanding of the inflamed lungs in asthma with the ultimate aim to evaluate potential therapies and suggest that regional and not global inflammation impacts lung function in asthma.
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Affiliation(s)
- Mamta Sumi
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio-44196, USA
| | - Rosemary Westcott
- Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio-44196, USA
| | - Eric Stuehr
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio-44196, USA
| | - Chaitali Ghosh
- Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio-44196, USA
| | - Dennis J. Stuehr
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio-44196, USA
| | - Arnab Ghosh
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio-44196, USA
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Li T, Ma X, Wang T, Tian W, Liu J, Shen W, Liu Y, Li Y, Zhang X, Ma J, Zhang X, Ma J, Wang H. Clostridium butyricum inhibits the inflammation in children with primary nephrotic syndrome by regulating Th17/Tregs balance via gut-kidney axis. BMC Microbiol 2024; 24:97. [PMID: 38521894 PMCID: PMC10960420 DOI: 10.1186/s12866-024-03242-3] [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: 11/16/2023] [Accepted: 02/27/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Primary nephrotic syndrome (PNS) is a common glomerular disease in children. Clostridium butyricum (C. butyricum), a probiotic producing butyric acid, exerts effective in regulating inflammation. This study was designed to elucidate the effect of C. butyricum on PNS inflammation through the gut-kidney axis. METHOD BALB/c mice were randomly divided into 4 groups: normal control group (CON), C. butyricum control group (CON+C. butyricum), PNS model group (PNS), and PNS with C. butyricum group (PNS+C. butyricum). The PNS model was established by a single injection of doxorubicin hydrochloride (DOX) through the tail vein. After 1 week of modeling, the mice were treated with C. butyricum for 6 weeks. At the end of the experiment, the mice were euthanized and associated indications were investigated. RESULTS Since the successful modeling of the PNS, the 24 h urine protein, blood urea nitrogen (BUN), serum creatinine (SCr), urine urea nitrogen (UUN), urine creatinine (UCr), lipopolysaccharides (LPS), pro-inflammatory interleukin (IL)-6, IL-17A were increased, the kidney pathological damage was aggravated, while a reduction of body weights of the mice and the anti-inflammatory IL-10 significantly reduced. However, these abnormalities could be dramatically reversed by C. butyricum treatment. The crucial Th17/Tregs axis in PNS inflammation also was proved to be effectively regulated by C. butyricum treatment. This probiotic intervention notably affected the expression levels of signal transducer and activator of transcription 3 (STAT3), Heme oxygenase-1 (HO-1) protein, and retinoic acid-related orphan receptor gamma t (RORγt). 16S rRNA sequencing showed that C. butyricum could regulate the composition of the intestinal microbial community and found Proteobacteria was more abundant in urine microorganisms in mice with PNS. Short-chain fatty acids (SCFAs) were measured and showed that C. butyricum treatment increased the contents of acetic acid, propionic acid, butyric acid in feces, acetic acid, and valeric acid in urine. Correlation analysis showed that there was a closely complicated correlation among inflammatory indicators, metabolic indicators, microbiota, and associated metabolic SCFAs in the gut-kidney axis. CONCLUSION C. butyricum regulates Th17/Tregs balance via the gut-kidney axis to suppress the immune inflammatory response in mice with PNS, which may potentially contribute to a safe and inexpensive therapeutic agent for PNS.
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Affiliation(s)
- Ting Li
- Department of Pediatrics, The First Clinical College of Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xiaolong Ma
- Department of Pediatrics, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Ting Wang
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Wenyan Tian
- Department of Gastroenterology, The First Clinical College of Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Jian Liu
- Department of Hepatobiliary, The First Clinical College of Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Wenke Shen
- Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yuanyuan Liu
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yiwei Li
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xiaoxu Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Junbai Ma
- Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xiaoxia Zhang
- College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China.
| | - Jinhai Ma
- Department of Pediatrics, General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
| | - Hao Wang
- Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
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Lv J, Zhou Y, Wang J, Wu Y, Yu Q, Zhang M, Su W, Tang Z, Wu Q, Wu M, Xia Z. Heme oxygenase-1 alleviates allergic airway inflammation by suppressing NF-κB-mediated pyroptosis of bronchial epithelial cells. FASEB J 2024; 38:e23472. [PMID: 38329323 DOI: 10.1096/fj.202300883rr] [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: 05/03/2023] [Revised: 12/26/2023] [Accepted: 01/24/2024] [Indexed: 02/09/2024]
Abstract
Allergic asthma development and pathogenesis are influenced by airway epithelial cells in response to allergens. Heme oxygenase-1 (HO-1), an inducible enzyme responsible for the breakdown of heme, has been considered an appealing target for the treatment of chronic inflammatory diseases. Herein, we report that alleviation of allergic airway inflammation by HO-1-mediated suppression of pyroptosis in airway epithelial cells (AECs). Using house dust mite (HDM)-induced asthma models of mice, we found increased gasdermin D (GSDMD) in the airway epithelium. In vivo administration of disulfiram, a specific inhibitor of pore formation by GSDMD, decreased thymic stromal lymphopoietin (TSLP) release, T helper type 2 immune response, alleviated airway inflammation, and reduced airway hyperresponsiveness (AHR). HO-1 induction by hemin administration reversed these phenotypes. In vitro studies revealed that HO-1 restrained GSDMD-mediated pyroptosis and cytokine TSLP release in AECs by binding Nuclear Factor-Kappa B (NF-κB) p65 RHD domain and thus controlling NF-κB-dependent pyroptosis. These data provide new therapeutic indications for purposing HO-1 to counteract inflammation, which contributes to allergic inflammation control.
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Affiliation(s)
- Jiajia Lv
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Zhou
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wang
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yujiao Wu
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianying Yu
- Department of Pulmonary, Children's Hospital of Soochow University, Suzhou, China
| | - Meng Zhang
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen Su
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiwei Tang
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qun Wu
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Wu
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Zhenwei Xia
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ge D, Chen Q, Xie X, Li Q, Yang Y. Unveiling the potent effect of vitamin D: harnessing Nrf2/HO-1 signaling pathways as molecular targets to alleviate urban particulate matter-induced asthma inflammation. BMC Pulm Med 2024; 24:55. [PMID: 38273268 PMCID: PMC10809564 DOI: 10.1186/s12890-024-02869-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Asthma is the most common allergic disease characterized by an inflammatory response in the airways. Mechanismly, urban particulate matter (PM) is the most widely air pollutant associated with increased asthma morbidity and airway inflammation. Current research found that vitamin D is an essential vitamin with anti-inflammatory, antioxidant and other medical efficacy. Inadequate or deficient vitamin D often leads to the pathogenesis and stability of asthma. NGF exacerbates airway inflammation in asthma by promoting smooth muscle cell proliferation and inducing the Th2 immune response. Activation of the Nrf2/HO-1 signaling pathway can exert a protective effect on the inflammatory response in bronchial asthma. However, the specific mechanism of this pathway in PM-involved asthmatic airway smooth muscle cells remains unclear. METHODS Mice were sensitized and challenged with Ovalbumin (OVA) to establish an asthma model. They were then exposed to either PM, vitamin D or a combination of both, and inflammatory responses were observed. Including, acetylcholine stimulation at different concentrations measured airway hyperresponsiveness in mice. Bronchoalveolar lavage fluid (BALF) and serum were collected for TNF-α, IL-1β, IL-6, and Nerve growth factor (NGF) analysis. Additionally, lung tissues underwent histopathological examination to observe alveolar structure and inflammatory cell infiltration. Specific ELISA kits were utilized to determine the levels of the inflammatory factors TNF-α, IL-1β, IL-6, and Nerve growth factor (NGF). Nrf2/HO-1 signaling pathways were examined by western blot analysis. Meanwhile, we constructed a cell system with low HO-1 expression by lentiviral transfection of airway smooth muscle cells. The changes of Nrf2, HO-1, and NGF were observed after the treatment of OVA, PM, and Vit D were given. RESULTS The in vivo results showed that vitamin D significantly alleviated pathological changes in lung tissue of PM-exposed mice models. Mechanismly, vitamin D decreased substantial inflammatory cell infiltration in lung tissue, as well as the number of inflammatory cells in BALF. Furthermore, vitamin D reduced the heightened inflammatory factors including of TNF-α, IL-1β, IL-6, and NGF caused by PM exposure, and triggered the activity of nucleus Nrf2 and HO-1 in PM-exposed asthmatic mice. Notably, knockdown HO-1 weakens the Vitamin D- mediated inhibition to pollution toxicity in asthma. Importantly, in vitro experiments on OVA-stimulated mice airway smooth muscle cells, the results showed that OVA and PM, respectively, reduced Nrf2/HO-1 and increased NGF's expression, while vitamin D reversed the process. And in the HO-1 knockdown cell line of Lenti-si-HO-1 ASMCs, OVA and PM reduced Nrf2's expression, while HO-1 and NGF's expression were unchanged. CONCLUSIONS The above results demastrate that vitamin D downregulated the inflammatory response and the expression of NGF by regulating the Nrf2/HO-1 signaling pathways in airway smooth muscle cells, thereby showing potent anti-inflammatory activity in asthma.
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Affiliation(s)
- Dandan Ge
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, Institute of Pediatrics, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Zhenhai Road No.55, Xiamen, 361003, China
| | - Qihong Chen
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, Institute of Pediatrics, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Zhenhai Road No.55, Xiamen, 361003, China
| | - Xiaohua Xie
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, Institute of Pediatrics, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Zhenhai Road No.55, Xiamen, 361003, China
| | - Qiyuan Li
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiang'an South Road, Xiamen, 361102, China
| | - Yungang Yang
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, Institute of Pediatrics, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Zhenhai Road No.55, Xiamen, 361003, China.
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Estarreja J, Caldeira G, Silva I, Mendes P, Mateus V. The Pharmacological Effect of Hemin in Inflammatory-Related Diseases: Protocol for a Systematic Review. JMIR Res Protoc 2023; 12:e48368. [PMID: 37971806 PMCID: PMC10690530 DOI: 10.2196/48368] [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: 04/20/2023] [Revised: 07/28/2023] [Accepted: 08/10/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Hemin is a commonly used drug in the treatment of acute attacks of porphyria, due to its capability of restoring normal levels of hemoproteins and respiratory pigments. In addition, this drug has demonstrated the capacity to induce the heme oxygenase (HO) enzyme. At the moment, there are 3 known HO isoenzymes in mammals: HO-1, HO-2, and HO-3. The first of these shows cytoprotective, antioxidant, and anti-inflammatory effects. Currently, medicines used in inflammatory disorders have increased toxicity, especially over longer time frames, which highlights the need to investigate new, safer options. Indeed, the current nonclinical evidence demonstrates the potential that hemin has a significant anti-inflammatory effect in several animal models of inflammation-related diseases, such as experimental colitis, without significant side effects. However, the underlying mechanism(s) are still not fully understood. In addition, past nonclinical studies have applied different therapeutic regimens, making it relatively difficult to understand which is optimal. According to the literature, there is a lack of review articles discussing this topic, highlighting the need for a summary and analysis of the available preclinical evidence to elucidate the abovementioned issues. Therefore, a qualitative synthesis of the current evidence is essential for the research and medical communities. OBJECTIVE This systematic review aims to summarize and analyze currently available nonclinical data to ascertain the potential anti-inflammatory effect of hemin in animal models. METHODS Throughout the development of this protocol, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The comprehensive search strategy will be carried out in MEDLINE (PubMed), Web of Science, and Scopus without any filters associated with publication date. Only in vivo, nonclinical studies that evaluated the potential anti-inflammatory effect of hemin will be included. The evaluated outcomes will be the observed clinical signs, inflammatory and other biochemical markers, and macroscopic and microscopic evaluations. To analyze the potential risk of bias, we will use the risk of bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). RESULTS Currently, it is not possible to disclose any results since the project is still in initial steps. More specifically, we are currently engaged in the identification of eligible articles through the application of the inclusion and exclusion criteria. The work was initiated in April 2023, and it is expected to be finished at the end of 2023. CONCLUSIONS Concerning the major gap in the literature regarding the underlying mechanism(s) and treatment-related properties, this systematic review will be essential to clearly summarize and critically analyze the nonclinical data available, promoting a clearer vision of the potential anti-inflammatory effect of hemin. TRIAL REGISTRATION PROSPERO CRD42023406160; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=406160. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/48368.
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Affiliation(s)
- João Estarreja
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Gonçalo Caldeira
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Inês Silva
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
| | - Priscila Mendes
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Vanessa Mateus
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
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Xu L, Cai J, Li C, Yang M, Duan T, Zhao Q, Xi Y, Sun L, He L, Tang C, Sun L. 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling. Mol Med 2023; 29:58. [PMID: 37095432 PMCID: PMC10127401 DOI: 10.1186/s10020-023-00631-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/08/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it remains elusive whether and how 4-OI contributes to the regulation of S-AKI. METHODS We employed a lipopolysaccharide (LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo. In vitro experiments, BUMPT cells, a murine renal tubular cell line, were conducted to examine the effects of 4-OI on inflammation, oxidative stress, and mitophagy. Moreover, STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OI-administrated state. RESULTS We demonstrate that 4-OI protects against S-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy. 4-OI significantly reduced the levels of Scr, BUN, Ngal as well as the tubular injury in LPS-induced AKI mice. 4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1β and NLRP3 in the septic kidney. 4-OI also reduced ROS levels, as well as cleaved caspase-3 and boosted antioxidants such as HO-1, and NQO1 in mice. In addition, the 4-OI treatment significantly promoted mitophagy. Mechanistically, 4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro. Molecular docking revealed the binding affinity of 4-OI towards STAT3. ML385, a specific Nrf2 inhibitor, partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and in vitro. Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro. CONCLUSION These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway, and inactivation of STAT3. Our study identifies 4-OI as a promising pharmacologic for S-AKI.
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Affiliation(s)
- Lujun Xu
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Juan Cai
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Chenrui Li
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Ming Yang
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Tongyue Duan
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Qing Zhao
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Yiyun Xi
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Liya Sun
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Liyu He
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Chengyuan Tang
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China
| | - Lin Sun
- Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, No.139 Renmin Middle Road, Changsha, Hunan, 410011, China.
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11
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Fang Z, Hu Y, Dai J, He L, He J, Xu B, Han X, Zhong F, Lan H, Wang Q. CS12192, a Novel JAK3/JAK1/TBK1 Inhibitor, Synergistically Enhances the Anti-Inflammation Effect of Methotrexate in a Rat Model of Rheumatoid Arthritis. Int J Mol Sci 2022; 23:ijms232113394. [PMID: 36362183 PMCID: PMC9658750 DOI: 10.3390/ijms232113394] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/22/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022] Open
Abstract
Rheumatoid arthritis (RA) is a common disease worldwide and is treated commonly with methotrexate (MTX). CS12192 is a novel JAK3 inhibitor discovered by Chipscreen Biosciences for the treatment of autoimmune diseases. In the present study, we examined the therapeutic effect of CS12192 against RA and explored if the combinational therapy of CS12192 and MTX produced a synergistic effect against RA in rat collagen-induced arthritis (CIA). Arthritis was induced in male Sprague-Dawley rats by two intradermal injections of bovine type II collagen (CII) and treated with MTX, CS12192, or the combination of CS12192 and MTX daily for two weeks. Effects of different treatments on arthritis score, X-ray score, pathology, and expression of inflammatory cytokines and biomarkers were examined. We found that treatment with either CS12192 or MTX produced a comparable therapeutic effect on CIA including: (1) significantly lowering the arthritis score, X-ray score, serum levels of rheumatic factor (RF), C-reactive protein (CRP), and anti-nuclear antibodies (ANA); (2) largely alleviating histopathological damage, reducing infiltration of Th17 cells while promoting Treg cells; (3) inhibiting the expression of inflammatory cytokines and chemokines such as IL-1β, TNF-α, IL-6, CCL2, and CXCL1. All these inhibitory effects were further improved by the combinational therapy with MTX and CS12192. Of importance, the combinational treatment also resulted in a marked switching of the Th17 to Treg and the M1 to M2 immune responses in synovial tissues of CIA. Thus, when compared to the monotherapy, the combination treatment with CS12192 and MTX produces a better therapeutic effect against CIA with a greater suppressive effect on T cells and macrophage-mediated joint inflammation.
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Affiliation(s)
- Zhengyu Fang
- Department of Rheumatism and Immunology, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Yiping Hu
- Department of Rheumatism and Immunology, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Jiajing Dai
- Clinical Research Institute, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
| | - Lianhua He
- Department of Rheumatism and Immunology, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Juan He
- Department of Rheumatism and Immunology, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Bihua Xu
- Department of Rheumatism and Immunology, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Xinle Han
- Clinical Research Institute, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
| | - Fubo Zhong
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Clinical Research Institute, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
| | - Huiyao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (H.L.); (Q.W.)
| | - Qingwen Wang
- Department of Rheumatism and Immunology, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Correspondence: (H.L.); (Q.W.)
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12
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Gong X, Zhu L, Liu J, Li C, Xu Z, Liu J, Zhang H. Exposure to traffic-related fine particulate matter 2.5 causes respiratory damage via peroxisome proliferator-activated receptor gamma-regulated inflammation. ENVIRONMENTAL TOXICOLOGY 2022; 37:2178-2188. [PMID: 35670047 DOI: 10.1002/tox.23584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 01/25/2022] [Accepted: 02/19/2022] [Indexed: 06/15/2023]
Abstract
Exposure to particulate matter 2.5 (PM2.5) potentially triggers airway inflammation. Peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to regulate inflammatory responses in diverse cell types. Therefore, this work investigated the mechanisms of PPARγ in regulating traffic-related PM2.5-induced airway inflammation. Using the diffusion flame burner soot generation, traffic-related PM2.5 was generated and adsorbed. BALB/c male mice and human bronchial epithelial cells (16-HBE) were exposed to PM2.5 alone or co-treatment with rosiglitazone (RSG), an agonist of PPARγ. To the end of exposure, bronchoalveolar lavage fluid (BALF), venous blood and arterial blood, trachea, bronchus and lung tissues were collected. The levels of IL-1β, IL-6, and IL-17 were detected by ELISA, and the cell types in BALF were counted. Hematoxylin-eosin (H&E) assay were used to analyze the pathological conditions of lung, bronchus, and pulmonary artery. Apoptosis was detected by TUNEL, and PPARγ expression in lung and bronchus was detected by immunohistochemical (IHC) staining. Western Blot was used to detect PPARγ, NF-kB, AP-1 and STAT3 expression in lung and bronchus. The viability was detected by MTT method. PM2.5 exposure caused pathological damage to the lung, bronchus and pulmonary artery tissue, which induced apoptosis of bronchial epithelial cells. PM2.5 exposure caused local inflammation of the whole body and airway. PPARγ expression increased after PM2.5 exposure. PM2.5 exposure regulated the downstream signaling pathways to affect the inflammatory response through PPARγ. Exposure to traffic-related PM2.5 caused respiratory damage via PPARγ-regulated inflammation.
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Affiliation(s)
- Xiaolei Gong
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Limin Zhu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinlong Liu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunxiang Li
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuoming Xu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinfen Liu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haibo Zhang
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Wang F, Yang Y, Li Z, Wang Y, Zhang Z, Zhang W, Mu Y, Yang J, Yu L, Wang M. Mannan-Binding Lectin Regulates the Th17/Treg Axis Through JAK/STAT and TGF-β/SMAD Signaling Against Candida albicans Infection. J Inflamm Res 2022; 15:1797-1810. [PMID: 35300210 PMCID: PMC8923702 DOI: 10.2147/jir.s344489] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 03/08/2022] [Indexed: 12/04/2022] Open
Abstract
Background Mannan-binding lectin (MBL) is a key molecule in innate immunity and activates the lectin complement pathway, which plays an important role in resisting Candida albicans (C. albicans) infection. However, the underlying mechanism of this resistance to infection remains unclear. Methods In this study, we investigated how MBL regulates the differentiation of CD4+ T cells into T helper type 17 (Th17) and T regulatory (Treg) cells against C. albicans in mice, as well as the underlying mechanisms. We generated MBL double-knockout (KO) mice and infected them with C. albicans by intraperitoneal injection. Results Compared with that in wild-type (WT) mice, the percentage of Th17 cells increased in MBL-null mice, whereas Treg cells decreased, indicating that MBL might regulate the Th17/Treg balance. In addition, in MBL-null mice, the expression levels of interleukin (IL)-17A, IL-21, and the master transcription factor of Th17 cells, RORγt, significantly increased. Conversely, IL-10, IL-2, and the Treg-specific transcription factor, Foxp3, decreased. Moreover, we found that the levels of TGF-β and IL-6 upregulated in MBL-null mice. Mechanistically, we found that MBL regulated the TGF-β/SMAD pathway through the inhibition of p-SMAD2 and promotion of p-SMAD3, and mediated the JAK/STAT pathway through the inhibition of p-JAK2 and p-STAT3 and promotion of p-JAK3 and p-STAT5. MBL double-KO mice showed a more severe inflammatory response and significantly lower survival rates with C. albicans infection. Conclusion These results suggest that MBL regulates the Th17/Treg cell balance to inhibit inflammatory responses, possibly via IL-6- and TGF-β-mediated JAK/STAT and TGF-β/SMAD signaling, and play an important role in anti-C. albicans infection.
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Affiliation(s)
- Fanping Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Yonghui Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Henan Center for Disease Control and Prevention, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Zhixin Li
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Yan Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Department of Laboratory Medicine, Luoyang Oriental Hospital, Luoyang, Henan, 471000, People’s Republic of China
| | - Zhenchao Zhang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Wei Zhang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Yonghui Mu
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Jingwen Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Lili Yu
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Mingyong Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- Correspondence: Mingyong Wang; Lili Yu, Email ;
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Immune Regulation of Heme Oxygenase-1 in Allergic Airway Inflammation. Antioxidants (Basel) 2022; 11:antiox11030465. [PMID: 35326116 PMCID: PMC8944570 DOI: 10.3390/antiox11030465] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/09/2022] [Accepted: 02/23/2022] [Indexed: 11/17/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is not only a rate-limiting enzyme in heme metabolism but is also regarded as a protective protein with an immunoregulation role in asthmatic airway inflammation. HO-1 exerts an anti-inflammation role in different stages of airway inflammation via regulating various immune cells, such as dendritic cells, mast cells, basophils, T cells, and macrophages. In addition, the immunoregulation role of HO-1 may differ according to subcellular locations.
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Yu X, Lv J, Wu J, Chen Y, Chen F, Wang L. The autoimmune encephalitis-related cytokine TSLP in the brain primes neuroinflammation by activating the JAK2-NLRP3 axis. Clin Exp Immunol 2022; 207:113-122. [PMID: 35020848 PMCID: PMC8802176 DOI: 10.1093/cei/uxab023] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/08/2021] [Accepted: 11/20/2021] [Indexed: 12/28/2022] Open
Abstract
NLRP3 inflammasome hyperactivation contributes to neuroinflammation in autoimmune disorders, but the underlying regulatory mechanism remains to be elucidated. We demonstrate that compared with wild-type (WT) mice, mice lacking thymic stromal lymphopoietin (TSLP) receptor (TSLPR) (Tslpr−/− mice) exhibit a significantly decreased experimental autoimmune encephalomyelitis (EAE) score, reduced CD4+ T cell infiltration, and restored myelin basic protein (MBP) expression in the brain after EAE induction by myelin oligodendrocyte glycoprotein35–55 (MOG35–55). TSLPR signals through Janus kinase (JAK)2, but not JAK1 or JAK3, to induce NLRP3 expression, and Tslpr−/− mice with EAE show decreased JAK2 phosphorylation and NLRP3 expression in the brain. JAK2 inhibition by ruxolitinib mimicked loss of TSLPR function in vivo and further decreased TSLP expression in the EAE mouse brain. The NLRP3 inhibitor MCC950 decreased CD4+ T cell infiltration, restored MBP expression, and decreased IL-1β and TSLP levels, verifying the pro-inflammatory role of NLRP3. In vitro experiments using BV-2 murine microglia revealed that TSLP directly induced NLRP3 expression, phosphorylation of JAK2 but not JAK1orJAK3, and IL-1β release, which were markedly inhibited by ruxolitinib. Furthermore, EAE induction led to an increase in the Th17 cell number, a decrease in the regulatory T (Treg) cell number in the blood, and an increase in the expression of the cytokine IL-17A in the WT mouse brain, which was drastically reversed in Tslpr−/− mice. In addition, ruxolitinib suppressed the increase in IL-17A expression in the EAE mouse brain. These findings identify TSLP as a prospective target for treating JAK2-NLRP3 axis-associated autoimmune inflammatory disorders.
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Affiliation(s)
- Xueyuan Yu
- Department of Clinical Laboratory, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Jiajia Lv
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Wu
- Department of Clinical Laboratory, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yong Chen
- Department of Clinical Laboratory, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Fei Chen
- Department of Clinical Laboratory, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Li Wang
- Department of Clinical Laboratory, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
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16
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Lv JJ, Su W, Chen XY, Yu Y, Xu X, Xu CD, Deng X, Huang JB, Wang XQ, Xiao Y. Autosomal recessive 333 base pair interleukin 10 receptor alpha subunit deletion in very early-onset inflammatory bowel disease. World J Gastroenterol 2021; 27:7705-7715. [PMID: 34908808 PMCID: PMC8641053 DOI: 10.3748/wjg.v27.i44.7705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/09/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Interleukin 10 receptor alpha subunit (IL10RA) dysfunction is the main cause of very early-onset inflammatory bowel disease (VEO-IBD) in East Asians.
AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.
METHODS From May 2016 to September 2020, four young patients with clinically diagnosed VEO-IBD were recruited. Before hospitalization, using targeted gene panel sequencing and trio-whole-exome sequencing (WES), three patients were found to harbor a IL10RA mutation (c.301C>T, p.R101W in one patient; c.537G>A, p.T179T in two patients), but WES results of the fourth patient were not conclusive. We performed whole-genome sequencing (WGS) on patients A and B and reanalyzed the data from patients C and D. Peripheral blood mononuclear cells (PBMCs) from patient D were isolated and stimulated with lipopolysaccharide (LPS), interleukin 10 (IL-10), and LPS + IL-10. Serum IL-10 levels in four patients and tumor necrosis factor-α (TNF-α) in the cell supernatant were determined by enzyme-linked immunosorbent assay. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.
RESULTS The four children in our study consisted of two males and two females. The age at disease onset ranged from 18 d to 9 mo. After hospitalization, a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data. Patient D was homozygous for the 333 bp deletion. All four patients had elevated serum IL-10 levels. In vitro, IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-α production induced by LPS. Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS + IL-10 in both healthy subjects and in patient D.
CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD, whereas the WES results were inconclusive.
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Affiliation(s)
- Jia-Jia Lv
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Wen Su
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Xiao-Yan Chen
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Yi Yu
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Xu Xu
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Chun-Di Xu
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Xing Deng
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Jie-Bin Huang
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Xin-Qiong Wang
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
| | - Yuan Xiao
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
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17
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Chen Z, Wang M, Yang S, Shi J, Ji T, Ding W, Jiang L, Fan Z, Chen J, Lu Y. Butyric Acid Protects Against Renal Ischemia-Reperfusion Injury by Adjusting the Treg/Th17 Balance via HO-1/p-STAT3 Signaling. Front Cell Dev Biol 2021; 9:733308. [PMID: 34796171 PMCID: PMC8593469 DOI: 10.3389/fcell.2021.733308] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022] Open
Abstract
Immune regulation plays a vital role in ischemia-reperfusion injury (IRI). Butyric acid (BA) has immunomodulatory effects in many diseases, but its immunomodulatory effects during renal IRI are still unclear. Our research shows that BA protected against IRI and significantly improved renal IRI in vivo. In vitro studies showed that BA inhibits Th17 cell differentiation and induces Treg cell differentiation. Mechanism studies have shown that heme oxygenase 1 (HO-1)/STAT3 signaling pathway was involved in the inhibitory effect of BA on Th17 cell differentiation. HO-1 inhibitors can significantly rescue the BA-mediated inhibition of Th17 cell differentiation. We confirmed that BA promotes the differentiation of Th17 cells into Treg cells by regulating the pathway and reduces renal IRI.
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Affiliation(s)
- Zhen Chen
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Miaomiao Wang
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Shikun Yang
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Chinese Academy of Medical Sciences, Nanjing, China
| | - Jian Shi
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Tianhao Ji
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Chinese Academy of Medical Sciences, Nanjing, China
| | - Wei Ding
- The Third Affiliated Hospital of Soochow University, Changzhou, China
- Wujin Hospital Affiliated With Jiangsu University, Changzhou, China
| | | | - Zhiwen Fan
- Department of Pathology, Affiliated Nanjing Drum Tower Hospital of Nanjing University School of Medicine, Nanjing, China
| | - Jing Chen
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yunjie Lu
- The Third Affiliated Hospital of Soochow University, Changzhou, China
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18
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Li Y, Ma K, Han Z, Chi M, Sai X, Zhu P, Ding Z, Song L, Liu C. Immunomodulatory Effects of Heme Oxygenase-1 in Kidney Disease. Front Med (Lausanne) 2021; 8:708453. [PMID: 34504854 PMCID: PMC8421649 DOI: 10.3389/fmed.2021.708453] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/31/2021] [Indexed: 01/23/2023] Open
Abstract
Kidney disease is a general term for heterogeneous damage that affects the function and the structure of the kidneys. The rising incidence of kidney diseases represents a considerable burden on the healthcare system, so the development of new drugs and the identification of novel therapeutic targets are urgently needed. The pathophysiology of kidney diseases is complex and involves multiple processes, including inflammation, autophagy, cell-cycle progression, and oxidative stress. Heme oxygenase-1 (HO-1), an enzyme involved in the process of heme degradation, has attracted widespread attention in recent years due to its cytoprotective properties. As an enzyme with known anti-oxidative functions, HO-1 plays an indispensable role in the regulation of oxidative stress and is involved in the pathogenesis of several kidney diseases. Moreover, current studies have revealed that HO-1 can affect cell proliferation, cell maturation, and other metabolic processes, thereby altering the function of immune cells. Many strategies, such as the administration of HO-1-overexpressing macrophages, use of phytochemicals, and carbon monoxide-based therapies, have been developed to target HO-1 in a variety of nephropathological animal models, indicating that HO-1 is a promising protein for the treatment of kidney diseases. Here, we briefly review the effects of HO-1 induction on specific immune cell populations with the aim of exploring the potential therapeutic roles of HO-1 and designing HO-1-based therapeutic strategies for the treatment of kidney diseases.
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Affiliation(s)
- Yunlong Li
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kuai Ma
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Zhongyu Han
- School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingxuan Chi
- School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiyalatu Sai
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhaolun Ding
- Department of Emergency Surgery, Shannxi Provincial People's Hospital, Xi'an, China
| | - Linjiang Song
- School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chi Liu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
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19
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Wu Y, Yu Q, Zhang M, Zhou Y, Su X, Wu M, Lv J, Xia Z. Hemin-primed dendritic cells suppress allergic airway inflammation through releasing extracellular vesicles. J Leukoc Biol 2021; 111:837-848. [PMID: 34296788 PMCID: PMC9292814 DOI: 10.1002/jlb.3a0321-175r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Hemin, a substrate of heme oxygenase (HO)‐1, induces HO‐1 expression on a variety of cells to exert anti‐oxidant and anti‐inflammatory roles. However, the role of HO‐1 in allergic diseases for dendritic cells (DCs) is not fully understood. Here, we report that HO‐1 modulates asthmatic airway inflammation by hemin‐treated DC‐released extracellular vesicles (DCEVs). Following induction of bone marrow‐derived DCs by hemin and then by house dust mite (HDM) in vitro, mouse CD4+ naïve T cells were cocultured with DCEVs to determine T helper (h) cell differentiation. C57BL/6 mice were sensitized by different stimuli‐induced DCEVs and challenged with HDM to analyze the changes of inflammatory cells and cytokines in the lung and bronchoalveolar lavage fluid. The results showed that hemin‐treated DCEVs (hemin‐DCEVs) express phosphatidylserine (PS), CD81, heat shock protein 70, and HO‐1, which facilitates regulatory T (Treg) cells differentiation in vitro and in vivo. In HDM‐induced asthmatic mouse model, hemin‐DCEVs inhalation reduced eosinophils infiltration and mucus secretion in the airway, decreased the levels of IL‐4, IL‐5, and IL‐13 in the lung and the number of Th2 cells in mediastinal lymph nodes (MLNs), and increased the number of Treg cells in MLNs. Thus, our study demonstrated, for the first time, that EVs from HO‐1‐overexpressing DCs alleviate allergic airway inflammation of eosinophilic asthma by potentiating Treg cells differentiation and limiting proinflammatory cytokine secretion, which expands our understanding of HO‐1 function, opening the door for HO‐1 inducer‐like hemin as a novel therapeutic strategy for asthma or other allergic diseases.
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Affiliation(s)
- Yujiao Wu
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianying Yu
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng Zhang
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Zhou
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Su
- Unit of Respiratory Infection and Immunity, Institute Pasteur of Shanghai Chinese Academy of Sciences, Shanghai, China
| | - Min Wu
- School of Medicine and Health Sciences, Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA
| | - Jiajia Lv
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenwei Xia
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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20
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Campbell NK, Fitzgerald HK, Dunne A. Regulation of inflammation by the antioxidant haem oxygenase 1. Nat Rev Immunol 2021; 21:411-425. [PMID: 33514947 DOI: 10.1038/s41577-020-00491-x] [Citation(s) in RCA: 250] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2020] [Indexed: 01/30/2023]
Abstract
Haem oxygenase 1 (HO-1), an inducible enzyme responsible for the breakdown of haem, is primarily considered an antioxidant, and has long been overlooked by immunologists. However, research over the past two decades in particular has demonstrated that HO-1 also exhibits numerous anti-inflammatory properties. These emerging immunomodulatory functions have made HO-1 an appealing target for treatment of diseases characterized by high levels of chronic inflammation. In this Review, we present an introduction to HO-1 for immunologists, including an overview of its roles in iron metabolism and antioxidant defence, and the factors which regulate its expression. We discuss the impact of HO-1 induction in specific immune cell populations and provide new insights into the immunomodulation that accompanies haem catabolism, including its relationship to immunometabolism. Furthermore, we highlight the therapeutic potential of HO-1 induction to treat chronic inflammatory and autoimmune diseases, and the issues faced when trying to translate such therapies to the clinic. Finally, we examine a number of alternative, safer strategies that are under investigation to harness the therapeutic potential of HO-1, including the use of phytochemicals, novel HO-1 inducers and carbon monoxide-based therapies.
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Affiliation(s)
- Nicole K Campbell
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. .,Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. .,Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
| | - Hannah K Fitzgerald
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Aisling Dunne
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,School of Medicine, Trinity College Dublin, Dublin, Ireland
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21
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Epithelial exosomal contactin-1 promotes monocyte-derived dendritic cell-dominant T-cell responses in asthma. J Allergy Clin Immunol 2021; 148:1545-1558. [PMID: 33957164 DOI: 10.1016/j.jaci.2021.04.025] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 04/07/2021] [Accepted: 04/13/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Exosomes have emerged as a vital player in cell-cell communication; however, whether airway epithelial cell (AEC)-generated exosomes participate in asthma development remains unknown. OBJECTIVE Our aims were to characterize the AEC-secreted exosomes and the potentially functional protein(s) that may contribute to the proinflammatory effects of AEC exosomes in the dendritic cell (DC)-dominant airway allergic models and to confirm their clinical significance in patients with asthma. METHODS Mice were treated with exosomes derived from house dust mite (HDM)-stimulated AECs (HDM-AEC-EXOs) or monocyte-derived DCs primed by HDM and/or contactin-1 (CNTN1). The numbers of DCs in the lung were determined by flow cytometry. Proteomic analysis of purified HDM-AEC-EXOs was performed. CNTN1 small interfering RNA was designed to probe its role in airway allergy, and γ-secretase inhibitor was used to determine involvement of the Notch pathway. RESULTS HDM-AEC-EXOs facilitate the recruitment, proliferation, migration, and activation of monocyte-derived DCs in cell culture and in mice. CNTN1 in exosomes is a critical player in asthma pathology. RNA interference-mediated silencing and pharmaceutical inhibitors characterize Notch2 receptor as necessary for relaying the CNTN1 signal to activate TH2 cell/TH17 cell immune response. Studies of patients with asthma also support existence of the CNTN1-Notch2 axis that has been observed in cell and mouse models. CONCLUSION This study's findings reveal a novel role for CNTN1 in asthma pathogenesis mediated through exosome secretion, indicating a potential strategy for the treatment of allergic airway inflammation.
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22
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Tackling Chronic Inflammation with Withanolide Phytochemicals-A Withaferin a Perspective. Antioxidants (Basel) 2020; 9:antiox9111107. [PMID: 33182809 PMCID: PMC7696210 DOI: 10.3390/antiox9111107] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.
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23
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Lin X, Lv J, Ge D, Bai H, Yang Y, Wu J. Heme oxygenase-1 alleviates eosinophilic inflammation by inhibiting STAT3-SOCS3 signaling. Pediatr Pulmonol 2020; 55:1440-1447. [PMID: 32297710 DOI: 10.1002/ppul.24759] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/28/2020] [Accepted: 03/18/2020] [Indexed: 01/05/2023]
Abstract
Airway inflammation of eosinophilic asthma (EA) attributes to Th2 response, leaving the role of Th17 response unknown. Signal transducer and activator of transcription 3 (STAT3) induce both suppressors of cytokine signaling 3 (SOCS3) and retinoic acid receptor-related orphan nuclear receptor γ (RORγt) to initiate Th17 cell differentiation which is inhibited by SOCS3, a negative feedback regulator of STAT3. Heme oxygenase-1 (HO-1) is a stress-responsive, cytoprotective, and immunoregulatory molecular. Two other isoforms of the enzyme includes HO-2 and HO-3. Because HO-2 does not exhibit stress-related upregulation and distributes mainly in nervous system and HO-3 shows a low enzymatic activity, we tested a hypothesized anti-inflammatory role for HO-1 in EA by inhibiting STAT3-SOCS3 signaling. Animal model was established with Ovalbumin in wild type Balb/C mice. Hemin or SNPP was intraperitoneally (IP) injected ahead of the animal model to induce or inhibit HO-1 expression. Airway inflammation was evaluated by bronchoalveolar lavage, hematoxyline and eosin staining, enzyme-linked immunosorbent assay, and Western blot analysis. In vivo results showed that HO-1 induction inhibited phosphorylation of STAT3 and expression of SOCS3 and RORγt, decreased Th2 and Th17 immune responses, and alleviated airway inflammation. In vitro results revealed that HO-1 inhibited phosphorylation of STAT3 and expression of SOCS3 in naive CD4+ T cells. These findings identify HO-1 induction as a potential therapeutic strategy for EA treatment by reducing STAT3 phosphorylation, STAT3-SOCS3-mediated Th2/Th17 immune responses, and ultimate allergic airway inflammation.
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Affiliation(s)
- Xiaoliang Lin
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jiajia Lv
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dandan Ge
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Haitao Bai
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Yungang Yang
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jinzhun Wu
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, Xiamen, China
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24
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Seiwert N, Heylmann D, Hasselwander S, Fahrer J. Mechanism of colorectal carcinogenesis triggered by heme iron from red meat. Biochim Biophys Acta Rev Cancer 2019; 1873:188334. [PMID: 31783067 DOI: 10.1016/j.bbcan.2019.188334] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the major tumor entities worldwide, with an increasing incidence in younger people. CRC formation is causally linked to various genetic, life-style and dietary risk factors. Among the ladder, the consumption of red meat has emerged as important risk factor contributing to CRC. A large body of evidence shows that heme iron is the critical component of red meat, which promotes colorectal carcinogenesis. In this review, we describe the uptake and cellular fate of both heme and inorganic iron in intestinal epithelial cells. Next, an overview on the DNA damaging properties of heme iron is provided, highlighting the DNA adducts relevant for CRC etiology. Moreover, heme triggered mechanisms leading to colonic hyperproliferation are presented, which are intimately linked to changes in the intestinal microbiota induced by heme. A special focus was set on the impact of heme iron on innate and adaptive immune cells, which could be relevant in the context of CRC. Finally, we recapitulate in vivo studies providing evidence for the tumor-promoting potential of dietary heme iron. Altogether, heme iron affects numerous key pathways involved in the pathogenesis of CRC.
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Affiliation(s)
- Nina Seiwert
- Department of Toxicology, University Medical Center Mainz, 55131 Mainz, Germany; Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, 35392 Giessen, Germany; Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Daniel Heylmann
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, 35392 Giessen, Germany
| | | | - Jörg Fahrer
- Department of Toxicology, University Medical Center Mainz, 55131 Mainz, Germany; Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, 35392 Giessen, Germany; Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany.
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25
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Goto K, Hiramoto K, Ooi K. Th2 and Th17 Induce Dry Skin in a Mouse Model of Arthritis. Biol Pharm Bull 2019; 42:468-474. [PMID: 30828078 DOI: 10.1248/bpb.b18-00803] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Skin dryness is a characteristic of rheumatoid arthritis (RA) model mice. However, the mechanism underlying the induction of dry skin by RA is unclear. We hypothesized that T helper (Th)2 and Th17 cells mediate this process. A mouse model of DBA/1JJmsSlc collagen-induced arthritis was treated with Th2 or Th17 cell inhibitor, and transepidermal water loss (TEWL) and the expression of markers associated with allergic reaction and inflammation were evaluated. TEWL and plasma levels of thymic stromal lymphopoietin, interleukin (IL)-6 and -17, and tumor necrosis factor (TNF)-α were increased in the arthritis mouse model compared to that in control mice. Administration of Th2 cell inhibitor abolished the increase in TEWL, IL-6, and TNF-α levels, whereas Th17 cell inhibitor reversed TEWL and decreased IL-17 level. Th2 and Th17 cells contribute to the induction of dry skin, but via distinct mechanisms.
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Affiliation(s)
- Kenji Goto
- Laboratory of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science.,Laboratory of Pathophysiology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Keiichi Hiramoto
- Laboratory of Pathophysiology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Kazuya Ooi
- Laboratory of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science.,Laboratory of Pathophysiology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science
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26
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Lv J, Su W, Yu Q, Zhang M, Di C, Lin X, Wu M, Xia Z. Heme oxygenase-1 protects airway epithelium against apoptosis by targeting the proinflammatory NLRP3-RXR axis in asthma. J Biol Chem 2018; 293:18454-18465. [PMID: 30333233 DOI: 10.1074/jbc.ra118.004950] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 09/05/2018] [Indexed: 12/19/2022] Open
Abstract
Asthma is thought to be caused by malfunction of type 2 T helper cell (Th2)-mediated immunity, causing excessive inflammation, mucus overproduction, and apoptosis of airway epithelial cells. Heme oxygenase-1 (HO-1) functions in heme catabolism and is both cytoprotective and anti-inflammatory. We hypothesized that this dual function may be related to asthma's etiology. Using primary airway epithelial cells (pAECs) and an asthma mouse model, we demonstrate that severe lung inflammation is associated with rapid pAEC apoptosis. Surprisingly, NOD-like receptor protein 3 (NLRP3) inhibition, retinoid X receptor (RXR) deficiency, and HO-1 induction were associated with abrogated apoptosis. MCC950, a selective small-molecule inhibitor of canonical and noncanonical NLRP3 activation, reduced RXR expression, leading to decreased pAEC apoptosis that was reversed by the RXR agonist adapalene. Of note, HO-1 induction in a mouse model of ovalbumin-induced eosinophilic asthma suppressed Th2 responses and reduced apoptosis of pulmonary pAECs. In vitro, HO-1 induction desensitized cultured pAECs to ovalbumin-induced apoptosis, confirming the in vivo observations. Critically, the HO-1 products carbon monoxide and bilirubin suppressed the NLRP3-RXR axis in pAECs. Furthermore, HO-1 impaired production of NLRP3-RXR-induced cytokines (interleukin [IL]-25, IL-33, thymic stromal lymphopoietin, and granulocyte-macrophage colony-stimulating factor) in pAECs and lungs. Finally, we demonstrate that HO-1 binds to the NACHT domain of NLRP3 and the RXRα and RXRβ subunits and that this binding is not reversed by Sn-protoporphyrin. Our findings indicate that HO-1 and its products are essential for pAEC survival to maintain airway epithelium homeostasis during NLRP3-RXR-mediated apoptosis and inflammation.
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Affiliation(s)
- Jiajia Lv
- From the Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China and
| | - Wen Su
- From the Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China and
| | - Qianying Yu
- From the Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China and
| | - Meng Zhang
- From the Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China and
| | - Caixia Di
- From the Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China and
| | - Xiaoliang Lin
- From the Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China and
| | - Min Wu
- the School of Medicine & Health Sciences, Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota 58202
| | - Zhenwei Xia
- From the Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China and
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27
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Lv J, Yu Q, Lv J, Di C, Lin X, Su W, Wu M, Xia Z. Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation. Eur J Immunol 2018; 48:1838-1850. [PMID: 30184256 PMCID: PMC6282509 DOI: 10.1002/eji.201847663] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/29/2018] [Accepted: 09/03/2018] [Indexed: 12/12/2022]
Abstract
Epithelial cells (ECs)-derived cytokines are induced by different stimuli through pattern recognition receptors (PRRs) to mount a type-2-cell-mediated immune response; however, the underlying mechanisms are poorly characterized. Here, we demonstrated asthmatic features in both primary bronchial epithelial cells (pBECs) and mouse model using several allergens including ovalbumin (OVA), house dust mite (HDM), or Alternaria alternata. We found that toll-like receptor 2 (TLR2) was highly induced in ECs but not dendritic cells (DCs) by various allergens, leading to recruitment of circulating basophils into the lung via C-C chemokine ligand-2 (CCL2). TLR2 expression increased thymic stromal lymphopoietin (TSLP) production through the NF-κB and JNK signaling pathways to extend the survival of recruited basophils and resident DCs in the lung, predisposing a type-2-cell-mediated airway inflammation. Conversely, TLR2 deficiency impaired secretion of TSLP and CCL2, decreased infiltration of lung basophils, and increased resistance to Th2 response. Blocking TSLP also phenocopied these phenomena. Our findings reveal a pro-inflammatory role of airway ECs through a TLR2-dependent TSLP production, which may have implication for treating allergic asthma.
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Affiliation(s)
- Jiajia Lv
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianying Yu
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Lv
- Department of Pediatrics, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Caixia Di
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoliang Lin
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen Su
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Wu
- School of Medicine & Health Sciences, Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota
| | - Zhenwei Xia
- Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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28
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Dai Y, Cheng X, Yu J, Chen X, Xiao Y, Tang F, Li Y, Wan S, Su W, Liang D. Hemin Promotes Corneal Allograft Survival Through the Suppression of Macrophage Recruitment and Activation. ACTA ACUST UNITED AC 2018; 59:3952-3962. [DOI: 10.1167/iovs.17-23327] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Ye Dai
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiaokang Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jianfeng Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiaoqing Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yichen Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Fen Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yingqi Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shangtao Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Dan Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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