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Xiao Z, Xie J, Zhao X, Chen X, Lu Y, Xu Y, Wu M, An L, Li Q. Role of Pyroptosis in inflammatory bowel disease. Int Immunopharmacol 2025; 155:114619. [PMID: 40209313 DOI: 10.1016/j.intimp.2025.114619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/21/2025] [Accepted: 04/03/2025] [Indexed: 04/12/2025]
Abstract
Inflammatory bowel disease (IBD) is a serious chronic condition marked by persistent and recurrent intestinal ulcers. Although the exact cause of IBD remains unclear, it is generally accepted that a complex interaction among dietary factors, gut microbiota, and immune responses in genetically predisposed individuals contributes to its development. Pyroptosis, an inflammatory form of programmed cell death activated by inflammasomes, is marked by the rupture of cell membranes and the subsequent release of inflammatory mediators. Emerging evidence indicates that pyroptosis plays a crucial role in the pathogenesis of IBD. Moderate pyroptosis activation can enhance intestinal immune defenses, while excessive inflammasome activation can trigger an inflammatory cascade, resulting in increased damage to intestinal tissues. This article reviews the molecular mechanisms underlying pyroptosis and highlights its role in the onset and progression of IBD. Furthermore, We explore recent advancements in IBD treatment, focusing on small molecule compounds that specifically target and inhibit pyroptosis.
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Affiliation(s)
- Zhiyi Xiao
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Jiling Xie
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Xun Zhao
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Xiangjun Chen
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Yihong Lu
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Yuanzhao Xu
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Manqing Wu
- Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Lingyue An
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.
| | - Qing Li
- Department of Gastroenterology and Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.
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Zhu QQ, Zhang Y, Cui L, Ma L, Sun KW. Downregulation of AQP9 Ameliorates NLRP3 Inflammasome-Dependent Inflammation and Pyroptosis in Crohn's Disease by Inhibiting the p38 MAPK Signaling Pathway. Mol Biotechnol 2025:10.1007/s12033-025-01382-z. [PMID: 39928266 DOI: 10.1007/s12033-025-01382-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/15/2025] [Indexed: 02/11/2025]
Abstract
Crohn's disease (CD), a complex gastrointestinal disorder, can be attributed to a combination of genetic factors, immune system dysfunction, and environmental triggers. Aquaporin 9 (AQP9) has been implicated in immunoregulation and inflammation in various conditions, yet its function in CD remains unclear. Herein, we investigated the contribution of AQP9 to CD pathogenesis and its impact on inflammation and pyroptosis. Bioinformatic analysis showed a significant increase in AQP9 expression (above 2.5-fold change) in CD patients compared to controls. In vitro experiments using human colonic epithelial cells (HT-29) demonstrated that AQP9 inhibition attenuated lipopolysaccharide (LPS)-induced cell damage, inflammatory cytokine secretion, and pyroptosis. Mechanistically, AQP9 silencing suppressed NLRP3 inflammasome activation, suggesting a role in regulating pyroptosis. AQP9 silencing inhibited p38 MAPK phosphorylation, indicating a direct involvement in modulating this inflammatory pathway. Furthermore, our findings indicate that AQP9 exacerbates inflammation and pyroptosis via activating the p38 MAPK signaling pathway, known to contribute to CD pathogenesis. In vivo studies using a murine model of CD-like colitis revealed that AQP9 inhibition led to about 45% reduction in colitis severity scores and about 30% decrease in the production of inflammatory cytokine by inactivating NLRP3 inflammasome and the p38 MAPK signaling. To sum up, our study highlights the involvement of AQP9 in CD pathogenesis through modulation of inflammation and pyroptosis via the NLRP3 inflammasome and p38 MAPK signaling pathway. Targeting AQP9 may offer a promising therapeutic approach for CD by suppressing inflammatory responses and preventing tissue damage.
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Affiliation(s)
- Qin-Qin Zhu
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), No. 185 Juqian Street, Tianning District, Changzhou, 213000, Jiangsu, China
| | - Yin Zhang
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), No. 185 Juqian Street, Tianning District, Changzhou, 213000, Jiangsu, China
| | - Lu Cui
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), No. 185 Juqian Street, Tianning District, Changzhou, 213000, Jiangsu, China
| | - Liang Ma
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), No. 185 Juqian Street, Tianning District, Changzhou, 213000, Jiangsu, China.
| | - Ke-Wen Sun
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), No. 185 Juqian Street, Tianning District, Changzhou, 213000, Jiangsu, China.
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Ji Y, Li P, Ning T, Yang D, Shi H, Dong X, Zhu S, Li P, Zhang S. PANoptosis-related genes: Molecular insights into immune dysregulation in ulcerative colitis. J Gastroenterol Hepatol 2025; 40:177-191. [PMID: 39568189 DOI: 10.1111/jgh.16804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/10/2024] [Accepted: 10/24/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND AND AIM Ulcerative colitis (UC) is a chronic inflammatory disease driven by immune dysregulation. PANoptosis, a novel form of programmed cell death, has been implicated in inflammatory diseases, but its specific role in UC remains unclear. This study aimed to identify PANoptosis-related genes (PRGs) that may contribute to immune dysregulation in UC. METHODS Using bioinformatics analysis of the GEO databases, we identified seven hub PRGs. Based on these genes, we developed a predictive model to differentiate UC patients from healthy controls, and evaluated its diagnostic performance using ROC curve analysis. We further conducted functional enrichment, GSVA, and immune infiltration analyses. Immunohistochemistry (IHC) was used to validate the expression of hub genes in UC patients. RESULTS The prediction model, based on the seven hub genes, exhibited diagnostic ability in discriminating UC patients from controls. Furthermore, these hub PRGs were found to be associated with immune cells, including dendritic cells, NK cells, macrophages, regulatory T cells (Tregs), and CD8+ T cells. They were also linked to key signaling pathways implicated in UC pathogenesis, such as IFNγ, TNFα, IL6-and JAK-STAT3, as well as hypoxia and apoptosis. Immunohistochemistry analysis validated the expression levels of hub PRGs in UC patients using paraffin sections of intestinal biopsy specimens. CONCLUSIONS This study identified PANoptosis-related genes with potential diagnostic value for UC and suggest that PANoptosis may contribute to the pathogenesis of UC by regulating specific immune cells and interacting with key signaling pathways. This highlights the potential importance of PANoptosis-related genes as therapeutic targets in UC management.
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Affiliation(s)
- Yuxiao Ji
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Pengchong Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Tingting Ning
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Deyi Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Haiyun Shi
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Xueyu Dong
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, China
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Zhao Y, Ma Y, Pei J, Zhao X, Jiang Y, Liu Q. Exploring Pyroptosis-related Signature Genes and Potential Drugs in Ulcerative Colitis by Transcriptome Data and Animal Experimental Validation. Inflammation 2024; 47:2057-2076. [PMID: 38656456 DOI: 10.1007/s10753-024-02025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/26/2024]
Abstract
Ulcerative colitis (UC) is an idiopathic, relapsing inflammatory disorder of the colonic mucosa. Pyroptosis contributes significantly to UC. However, the molecular mechanisms of UC remain unexplained. Herein, using transcriptome data and animal experimental validation, we sought to explore pyroptosis-related molecular mechanisms, signature genes, and potential drugs in UC. Gene profiles (GSE48959, GSE59071, GSE53306, and GSE94648) were selected from the Gene Expression Omnibus (GEO) database, which contained samples derived from patients with active and inactive UC, as well as health controls. Gene Set Enrichment Analysis (GSEA), Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on microarrays to unravel the association between UC and pyroptosis. Then, differential expressed genes (DEGs) and pyroptosis-related DEGs were obtained by differential expression analyses and the public database. Subsequently, pyroptosis-related DEGs and their association with the immune infiltration landscape were analyzed using the CIBERSORT method. Besides, potential signature genes were selected by machine learning (ML) algorithms, and then validated by testing datasets which included samples of colonic mucosal tissue and peripheral blood. More importantly, the potential drug was screened based on this. And these signature genes and the drug effect were finally observed in the animal experiment. GSEA and KEGG enrichment analyses on key module genes derived from WGCNA revealed a close association between UC and pyroptosis. Then, a total of 20 pyroptosis-related DEGs of UC and 27 pyroptosis-related DEGs of active UC were screened. Next, 6 candidate genes (ZBP1, AIM2, IL1β, CASP1, TLR4, CASP11) in UC and 2 candidate genes (TLR4, CASP11) in active UC were respectively identified using the binary logistic regression (BLR), least absolute shrinkage and selection operator (LASSO), random forest (RF) analysis and artificial neural network (ANN), and these genes also showed high diagnostic specificity for UC in testing sets. Specially, TLR4 was elevated in UC and further elevated in active UC. The results of the drug screen revealed that six compounds (quercetin, cyclosporine, resveratrol, cisplatin, paclitaxel, rosiglitazone) could target TLR4, among which the effect of quercetin on intestinal pathology, pyroptosis and the expression of TLR4 in UC and active UC was further determined by the murine model. These findings demonstrated that pyroptosis may promote UC, and especially contributes to the activation of UC. Pyroptosis-related DEGs offer new ideas for the diagnosis of UC. Besides, quercetin was verified as an effective treatment for pyroptosis and intestinal inflammation. This study might enhance our comprehension on the pathogenic mechanism and diagnosis of UC and offer a treatment option for UC.
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Affiliation(s)
- Yang Zhao
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yiming Ma
- Macau University of Science and Technology, Macau, 999078, China
| | - Jianing Pei
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Xiaoxuan Zhao
- Department of Traditional Chinese Medicine (TCM) Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China
| | - Yuepeng Jiang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Qingsheng Liu
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China.
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Yan Q, Feng Z, Jiang B, Yao J. Biological functions of connexins in the development of inflammatory bowel disease. Scand J Gastroenterol 2024; 59:142-149. [PMID: 37837320 DOI: 10.1080/00365521.2023.2267713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/25/2023] [Accepted: 10/01/2023] [Indexed: 10/16/2023]
Abstract
Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammatory diseases with unknown etiology. Gap junctions composed of connexins (Cxs) have been recently validated as an important factor in the development of IBD. Under IBD-induced inflammatory response in the gut, gap junctions connect multiple signaling pathways involved in the interaction between inflammatory cells with other intestinal cells, which altogether mediate the development of IBD. This paper is a narrative review aiming to comprehensively elucidate the biological function of connexins, especially the ubiquitously and predominantly expressed Cx43, in the pathogenesis of IBD.
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Affiliation(s)
- Qiaojing Yan
- Colorectal Surgery Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Jiangsu Province Traditional Chinese Medicine Innovation Center for Anorectal Disease, Nanjing, China
| | - Zhiling Feng
- Colorectal Surgery Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Bin Jiang
- Colorectal Surgery Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Jiangsu Province Traditional Chinese Medicine Innovation Center for Anorectal Disease, Nanjing, China
| | - Jian Yao
- Division of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Japan
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Electrolyzed Hydrogen Water Alleviates Abdominal Pain through Suppression of Colonic Tissue Inflammation in a Rat Model of Inflammatory Bowel Disease. Nutrients 2022; 14:nu14214451. [PMID: 36364715 PMCID: PMC9655279 DOI: 10.3390/nu14214451] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/14/2022] [Accepted: 10/20/2022] [Indexed: 01/24/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive tract and is typically accompanied by characteristic symptoms, such as abdominal pain, diarrhea, and bloody stool, severely deteriorating the quality of the patient's life. Electrolyzed hydrogen water (EHW) has been shown to alleviate inflammation in several diseases, such as renal disease and polymyositis/dermatomyositis. To investigate whether and how daily EHW consumption alleviates abdominal pain, the most common symptom of IBD, we examined the antioxidative and anti-inflammatory effects of EHW in an IBD rat model, wherein colonic inflammation was induced by colorectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). We found that EHW significantly alleviated TNBS-induced abdominal pain and tissue inflammation. Moreover, the production of proinflammatory cytokines in inflamed colon tissue was also decreased significantly. Meanwhile, the overproduction of reactive oxygen species (ROS), which is intricately involved in intestinal inflammation, was significantly suppressed by EHW. Additionally, expression of S100A9, an inflammatory biomarker of IBD, was significantly suppressed by EHW. These results suggest that the EHW prevented the overproduction of ROS due to its powerful free-radical scavenging ability and blocked the crosstalk between oxidative stress and inflammation, thereby suppressing colonic inflammation and alleviating abdominal pain.
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Zhao J, Sun Y, Yang H, Qian J, Zhou Y, Gong Y, Dai Y, Jiao Y, Zhu W, Wang H, Lin Z, Tang L. PLGA-microspheres-carried circGMCL1 protects against Crohn's colitis through alleviating NLRP3 inflammasome-induced pyroptosis by promoting autophagy. Cell Death Dis 2022; 13:782. [PMID: 36088391 PMCID: PMC9464224 DOI: 10.1038/s41419-022-05226-5] [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: 06/03/2022] [Revised: 08/25/2022] [Accepted: 08/31/2022] [Indexed: 01/21/2023]
Abstract
This study aimed to at explore exploring the biological functions of dysregulated circRNA in Crohn's disease (CD) pathogenesis, with the overarching goal of and providing potential novel therapeutic targets. CircRNA microarray and quantitative real time-polymerase chain reaction (qRT-PCR) analyses were performed to investigate and verify the candidate dysregulated circRNA. The Next, clinical, in vivo, and in vitro studies were performed to investigate explore the biological function and mechanisms of the candidate circRNA in CD. The therapeutic effect of poly (lactic-co-glycolic acid)-microspheres (PLGA MSs)-carried oe-circGMCL1 in experimental colitis models of IL-10 knock-out mice was assessed. CircGMCL1 was identified as the candidate circRNA by microarray and qRT-PCR analyses. Results showed that circGMCL1 expression was negatively correlated with CD-associated inflammatory indices, suggesting that it is a CD-associated circRNA. Microarray and bioinformatics analyses identified miR-124-3p and Annexin 7 (ANXA7) as its downstream mechanisms. The in vitro studies revealed that circGMCL1 mediates its effects on autophagy and NLRP3 inflammasome-mediated pyroptosis in epithelial cells through the ceRNA network. Moreover, the in vivo studies identified the therapeutic effect of PLGA MSs-carried oe-circGMCL1 in experimental colitis models. This study suggests that circGMCL1 protects intestinal barrier function against Crohn's colitis through alleviating NLRP3 inflammasome-mediated epithelial pyroptosis by promoting autophagy through regulating ANXA7 via sponging miR-124-3p. Therefore, circGMCL1 can serve as a potential biological therapeutic target for Crohn's colitis.
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Affiliation(s)
- Jie Zhao
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery and Central Laboratory, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Ye Sun
- grid.412676.00000 0004 1799 0784Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haojun Yang
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Jun Qian
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yan Zhou
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery and Central Laboratory, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yu Gong
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yi Dai
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yuwen Jiao
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Honggang Wang
- grid.89957.3a0000 0000 9255 8984Department of General Surgery, Taizhou People’s Hospital, Taizhou Clinical Medical School of Nanjing Medical University, Nanjing, China
| | - Zhiliang Lin
- grid.412538.90000 0004 0527 0050Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People’s Hospital, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Liming Tang
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
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Gong M, Zhang F, Miao Y, Niu J. Advances of Heat Shock Family in Ulcerative Colitis. Front Pharmacol 2022; 13:869930. [PMID: 35645809 PMCID: PMC9133716 DOI: 10.3389/fphar.2022.869930] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Abstract
Ulcerative Colitis (UC) is a non-specific and chronic inflammatory disease of colonic mucosa whose exact etiology and mechanisms remain unclear. The incidence rate of UC is increasing year by year worldwide. What followed is that the medical costs are also rising rapidly. Therefore, it is urgent to understand the pathogenesis and find promising therapeutic targets for UC. Intestinal mucosal homeostasis is essential for normal bowel function, and its imbalance may be an important pathogenesis of UC. Endogenous homeostatic regulators play roles in repairing intestinal mucosa injury after stress. Heat shock family proteins are essential endogenous homeostasis factors. They can inhibit inflammation, regulate intestinal epithelial cells’ survival and death, and promote mucosal healing. Thus, they play important roles in sustaining intestinal mucosal homeostasis and protecting against UC progression. However, the heat shock family may promote UC carcinogenesis. Here, we summarize the advances in the research of the functions of the heat shock family in UC. And this review is an attempt to light on the etiopathogenesis of UC, highlighting the endogenous protective mechanisms, hoping to provide a novel therapeutic target for UC treatment.
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Affiliation(s)
- Min Gong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Fengrui Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Yinglei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
- *Correspondence: Yinglei Miao, ; Junkun Niu,
| | - Junkun Niu
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
- *Correspondence: Yinglei Miao, ; Junkun Niu,
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Sarmento A, Simões CD. Gut Microbiota Dysbiosis and Chronic Intestinal Inflammation. COMPREHENSIVE GUT MICROBIOTA 2022:423-441. [DOI: 10.1016/b978-0-12-819265-8.00057-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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10
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Su RC, Breidenbach JD, Alganem K, Khalaf FK, French BW, Dube P, Malhotra D, McCullumsmith R, Presloid JB, Wooten RM, Kennedy DJ, Haller ST. Microcystin-LR (MC-LR) Triggers Inflammatory Responses in Macrophages. Int J Mol Sci 2021; 22:9939. [PMID: 34576099 PMCID: PMC8472269 DOI: 10.3390/ijms22189939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/31/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
We were the first to previously report that microcystin-LR (MC-LR) has limited effects within the colons of healthy mice but has toxic effects within colons of mice with pre-existing inflammatory bowel disease. In the current investigation, we aimed to elucidate the mechanism by which MC-LR exacerbates colitis and to identify effective therapeutic targets. Through our current investigation, we report that there is a significantly greater recruitment of macrophages into colonic tissue with pre-existing colitis in the presence of MC-LR than in the absence of MC-LR. This is seen quantitatively through IHC staining and the enumeration of F4/80-positive macrophages and through gene expression analysis for Cd68, Cd11b, and Cd163. Exposure of isolated macrophages to MC-LR was found to directly upregulate macrophage activation markers Tnf and Il1b. Through a high-throughput, unbiased kinase activity profiling strategy, MC-LR-induced phosphorylation events were compared with potential inhibitors, and doramapimod was found to effectively prevent MC-LR-induced inflammatory responses in macrophages.
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Affiliation(s)
- Robin C. Su
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Joshua D. Breidenbach
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Khaled Alganem
- Department of Neuroscience, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (K.A.); (R.M.)
| | - Fatimah K. Khalaf
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Benjamin W. French
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Prabhatchandra Dube
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Deepak Malhotra
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Robert McCullumsmith
- Department of Neuroscience, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (K.A.); (R.M.)
- Neurosciences Center, Promedica, Toledo, OH 43614, USA
| | - John B. Presloid
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (J.B.P.); (R.M.W.)
| | - R. Mark Wooten
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (J.B.P.); (R.M.W.)
| | - David J. Kennedy
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Steven T. Haller
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
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Nortunen M, Väkiparta N, Porvari K, Saarnio J, Karttunen TJ, Huhta H. Pathophysiology of reflux oesophagitis: role of Toll-like receptors 2 and 4 and Farnesoid X receptor. Virchows Arch 2021; 479:285-293. [PMID: 33686512 PMCID: PMC8364528 DOI: 10.1007/s00428-021-03066-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 01/15/2021] [Accepted: 02/18/2021] [Indexed: 11/28/2022]
Abstract
The pathogenesis of gastroesophageal reflux disease (GERD) is not fully understood. It involves the activation of mucosal immune-mediated and inflammatory responses. Toll-like receptors (TLR) 2 and TLR4 are pattern-recognition receptors of the innate immune system; they recognize microbial and endogenous ligands. Farnesoid X receptor (FXR) is a bile acid receptor that regulates the inflammatory response. We aimed to evaluate TLR2, TLR4 and FXR expression patterns in GERD. We re-evaluated 84 oesophageal biopsy samples according to the global severity (GS) score, including 26 cases with histologically normal oesophagus, 28 with histologically mild oesophagitis and 30 with severe oesophagitis. We used immunohistochemistry and in situ hybridization to assess the expression patterns of TLR2, TLR4 and FXR in oesophageal squamous cells. Immunohistochemistry showed that nuclear and cytoplasmic TLR2 was expressed predominantly in the basal layer of normal oesophageal epithelium. In oesophagitis, TLR2 expression increased throughout the epithelium, and the superficial expression was significantly more intensive compared to normal epithelium, p <0.01. Nuclear and cytoplasmic TLR4 was expressed throughout the thickness of squamous epithelium, with no change in oesophagitis. FXR was expressed in the nuclei of squamous cells, and the intensity of the expression increased significantly in oesophagitis (p <0.05). FXR expression correlated with basal TLR2. In situ hybridization confirmed the immunohistochemical expression patterns of TLR2 and TLR4. In GERD, TLR2, but not TLR4, expression was upregulated which indicates that innate immunity is activated according to a specific pattern in GERD. FXR expression was increased in GERD and might have a regulatory connection to TLR2.
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Affiliation(s)
- Minna Nortunen
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014, Oulu, Finland.
- Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, Oulu, Finland.
- Department of Surgery, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
| | - Nina Väkiparta
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014, Oulu, Finland
| | - Katja Porvari
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014, Oulu, Finland
| | - Juha Saarnio
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014, Oulu, Finland
- Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, Oulu, Finland
- Department of Surgery, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland
| | - Tuomo J Karttunen
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014, Oulu, Finland
| | - Heikki Huhta
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014, Oulu, Finland
- Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, Oulu, Finland
- Department of Surgery, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland
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12
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Drobny A, Ngo PA, Neurath MF, Zunke F, López-Posadas R. Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease. Front Med (Lausanne) 2021; 8:655123. [PMID: 34368179 PMCID: PMC8339315 DOI: 10.3389/fmed.2021.655123] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/14/2021] [Indexed: 12/18/2022] Open
Abstract
Intestinal symptoms, such as nausea, vomiting, and constipation, are common in Parkinson's disease patients. These clinical signs normally appear years before the diagnosis of the neurodegenerative disease, preceding the occurrence of motor manifestations. Moreover, it is postulated that Parkinson's disease might originate in the gut, due to a response against the intestinal microbiota leading to alterations in alpha-synuclein in the intestinal autonomic nervous system. Transmission of this protein to the central nervous system is mediated potentially via the vagus nerve. Thus, deposition of aggregated alpha-synuclein in the gastrointestinal tract has been suggested as a potential prodromal diagnostic marker for Parkinson's disease. Interestingly, hallmarks of chronic intestinal inflammation in inflammatory bowel disease, such as dysbiosis and increased intestinal permeability, are also observed in Parkinson's disease patients. Additionally, alpha-synuclein accumulations were detected in the gut of Crohn's disease patients. Despite a solid association between neurodegenerative diseases and gut inflammation, it is not clear whether intestinal alterations represent cause or consequence of neuroinflammation in the central nervous system. In this review, we summarize the bidirectional communication between the brain and the gut in the context of Parkinson's disease and intestinal dysfunction/inflammation as present in inflammatory bowel disease. Further, we focus on the contribution of intestinal epithelium, the communication between intestinal epithelial cells, microbiota, immune and neuronal cells, as well as mechanisms causing alterations of epithelial integrity.
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Affiliation(s)
- Alice Drobny
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Phuong A Ngo
- Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Markus F Neurath
- Medicine 1, University Hospital Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Friederike Zunke
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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13
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Zhou X, Zhang D, Qi W, Hong T, Xiong T, Wu T, Geng F, Xie M, Nie S. Exopolysaccharides from Lactobacillus plantarum NCU116 Facilitate Intestinal Homeostasis by Modulating Intestinal Epithelial Regeneration and Microbiota. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:7863-7873. [PMID: 34236844 DOI: 10.1021/acs.jafc.1c01898] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Regeneration of epithelia is crucial for maintaining the intestinal barrier and homeostasis. Our previous work showed that exopolysaccharides from Lactobacillus plantarum NCU116 (EPS116) regulated the barrier function and homeostasis of the intestine; however, the relevant mechanisms remain obscure. Therefore, we sought to explore the role of EPS116 in promoting intestinal epithelial regeneration. Our data showed that the administration of EPS116 markedly ameliorated inflammatory bowel disease-related phenotypes and promoted the regeneration of crypts in the colon of colitis mice. The results of immunofluorescence and reverse transcription-quantitative polymerase chain reaction experiments indicated that EPS116 strikingly increased the number of intestinal stem cells (ISCs) and the expression of differentiation markers for goblet cells, enterocytes, and enteroendocrine cells in the mouse colon. Intestinal microbiota analysis showed that EPS116 increased microbial populations associated with intestinal regeneration and glycan metabolism. Therefore, the present study revealed a novel model that EPS116 promoted the intestinal homeostasis through modulating the proliferation and differentiation of ISCs and altering the gut microbiota profile.
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Affiliation(s)
- Xingtao Zhou
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang, Jiangxi 330047, China
| | - Duoduo Zhang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang, Jiangxi 330047, China
| | - Wucheng Qi
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang, Jiangxi 330047, China
| | - Tao Hong
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang, Jiangxi 330047, China
| | - Tao Xiong
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang, Jiangxi 330047, China
| | - Tingqin Wu
- Department of Cell Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Fang Geng
- Key Laboratory of Coarse Cereal Processing (Ministry of Agriculture and Rural Affairs), School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
| | - Mingyong Xie
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang, Jiangxi 330047, China
| | - Shaoping Nie
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang, Jiangxi 330047, China
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14
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Udayan S, Buttó LF, Rossini V, Velmurugan J, Martinez-Lopez M, Sancho D, Melgar S, O'Toole PW, Nally K. Macrophage cytokine responses to commensal Gram-positive Lactobacillus salivarius strains are TLR2-independent and Myd88-dependent. Sci Rep 2021; 11:5896. [PMID: 33723368 PMCID: PMC7961041 DOI: 10.1038/s41598-021-85347-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 02/26/2021] [Indexed: 01/31/2023] Open
Abstract
The mechanisms through which cells of the host innate immune system distinguish commensal bacteria from pathogens are currently unclear. Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) expressed by host cells which recognize microbe-associated molecular patterns (MAMPs) common to both commensal and pathogenic bacteria. Of the different TLRs, TLR2/6 recognize bacterial lipopeptides and trigger cytokines responses, especially to Gram-positive and Gram-negative pathogens. We report here that TLR2 is dispensable for triggering macrophage cytokine responses to different strains of the Gram-positive commensal bacterial species Lactobacillus salivarius. The L. salivarius UCC118 strain strongly upregulated expression of the PRRs, Mincle (Clec4e), TLR1 and TLR2 in macrophages while downregulating other TLR pathways. Cytokine responses triggered by L. salivarius UCC118 were predominantly TLR2-independent but MyD88-dependent. However, macrophage cytokine responses triggered by another Gram-positive commensal bacteria, Bifidobacterium breve UCC2003 were predominantly TLR2-dependent. Thus, we report a differential requirement for TLR2-dependency in triggering macrophage cytokine responses to different commensal Gram-positive bacteria. Furthermore, TNF-α responses to the TLR2 ligand FSL-1 and L. salivarius UCC118 were partially Mincle-dependent suggesting that PRR pathways such as Mincle contribute to the recognition of MAMPs on distinct Gram-positive commensal bacteria. Ultimately, integration of signals from these different PRR pathways and other MyD88-dependent pathways may determine immune responses to commensal bacteria at the host-microbe interface.
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Affiliation(s)
- Sreeram Udayan
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | | | - Valerio Rossini
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | - Maria Martinez-Lopez
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - David Sancho
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Silvia Melgar
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Paul W O'Toole
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Microbiology, University College Cork, Cork, Ireland
| | - Ken Nally
- APC Microbiome Ireland, University College Cork, Cork, Ireland.
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
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15
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Wagatsuma K, Nakase H. Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis. Int J Mol Sci 2020; 21:ijms21218145. [PMID: 33143375 PMCID: PMC7662299 DOI: 10.3390/ijms21218145] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 02/08/2023] Open
Abstract
The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease.
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16
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Ye L, Li G, Goebel A, Raju AV, Kong F, Lv Y, Li K, Zhu Y, Raja S, He P, Li F, Mwangi SM, Hu W, Srinivasan S. Caspase-11-mediated enteric neuronal pyroptosis underlies Western diet-induced colonic dysmotility. J Clin Invest 2020; 130:3621-3636. [PMID: 32484462 PMCID: PMC7324173 DOI: 10.1172/jci130176] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 03/24/2020] [Indexed: 02/06/2023] Open
Abstract
Enteric neuronal degeneration, as seen in inflammatory bowel disease, obesity, and diabetes, can lead to gastrointestinal dysmotility. Pyroptosis is a novel form of programmed cell death but little is known about its role in enteric neuronal degeneration. We observed higher levels of cleaved caspase-1, a marker of pyroptosis, in myenteric ganglia of overweight and obese human subjects compared with normal-weight subjects. Western diet-fed (WD-fed) mice exhibited increased myenteric neuronal pyroptosis, delayed colonic transit, and impaired electric field stimulation-induced colonic relaxation responses. WD increased TLR4 expression and cleaved caspase-1 in myenteric nitrergic neurons. Overactivation of nitrergic neuronal NF-κB signaling resulted in increased pyroptosis and delayed colonic motility. In caspase-11-deficient mice, WD did not induce nitrergic myenteric neuronal pyroptosis and colonic dysmotility. To understand the contributions of saturated fatty acids and bacterial products to the steps leading to enteric neurodegeneration, we performed in vitro experiments using mouse enteric neurons. Palmitate and lipopolysaccharide (LPS) increased nitrergic, but not cholinergic, enteric neuronal pyroptosis. LPS gained entry to the cytosol in the presence of palmitate, activating caspase-11 and gasdermin D, leading to pyroptosis. These results support a role of the caspase-11-mediated pyroptotic pathway in WD-induced myenteric nitrergic neuronal degeneration and colonic dysmotility, providing important therapeutic targets for enteric neuropathy.
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Affiliation(s)
- Lan Ye
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Ge Li
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Anna Goebel
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Abhinav V. Raju
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Feng Kong
- Second Hospital of Shandong University, Jinan, China
| | - Yanfei Lv
- Second Hospital of Shandong University, Jinan, China
| | - Kailin Li
- Second Hospital of Shandong University, Jinan, China
| | - Yuanjun Zhu
- Center for Metabolic Disease Research, Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA
| | - Shreya Raja
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Peijian He
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Fang Li
- Center for Metabolic Disease Research, Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA
| | - Simon Musyoka Mwangi
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Wenhui Hu
- Center for Metabolic Disease Research, Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA
| | - Shanthi Srinivasan
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
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17
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Eyking A, Ferber F, Köhler S, Reis H, Cario E. TRIM58 Restrains Intestinal Mucosal Inflammation by Negatively Regulating TLR2 in Myeloid Cells. THE JOURNAL OF IMMUNOLOGY 2019; 203:1636-1649. [PMID: 31383741 DOI: 10.4049/jimmunol.1900413] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/08/2019] [Indexed: 12/19/2022]
Abstract
Balanced control of innate immune signaling in the intestine represents an important host defense mechanism to avoid inappropriate responses that may exacerbate mucosal injury in acute inflammation. In this study, we report that TRIM58, a RING E3-ubiquitin ligase, associates with TLR2. The interaction was found in a yeast two-hybrid screen (human leukocyte and mononuclear library) and confirmed by coimmunoprecipitation of tagged and endogenous proteins. TRIM58 was predominantly expressed by murine and human myeloid-derived cells. Stimulation with a TLR2 ligand modulated TRIM58 synthesis in myeloid cells. Overexpression of TRIM58, but only in presence of the RING domain, promoted proteasome-dependent degradation of TLR2, inhibiting its signaling activity. Genetic deletion of Trim58 in mice (Trim58 -/-) led to impaired resolution of acute dextran sodium sulfate-induced colitis, which was characterized by delayed recovery from colonic injury and associated with enhanced expression of TLR2 protein and proinflammatory cyto/chemokine production in inflamed colons. Using myeloid cell-specific deletion of Trim58 in mice, we demonstrated that the myeloid cell compartment was responsible for early colitis acceleration in Trim58 deficiency. In vitro studies revealed that Trim58 -/- myeloid cells, which showed constitutive upregulation of TLR2 protein, overreacted to a proinflammatory milieu (TNF-α and IFN-γ) with increased IL-1β protein production, which mechanistically depended on Tlr2 Finally, we found that TRIM58 mRNA and protein expression levels were reduced in colonic specimens from patients with ulcerative colitis. In conclusion, we identify TRIM58 as a novel negative mediator of innate immune control and mucosal homeostasis via TLR2 signaling. Dysfunction of TRIM58 in myeloid cells may contribute to ulcerative colitis pathogenesis.
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Affiliation(s)
- Annette Eyking
- Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, 45147 Essen, Germany.,Medical School, University of Duisburg-Essen, 45147 Essen, Germany; and
| | - Frederike Ferber
- Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, 45147 Essen, Germany.,Medical School, University of Duisburg-Essen, 45147 Essen, Germany; and
| | - Stefanie Köhler
- Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, 45147 Essen, Germany.,Medical School, University of Duisburg-Essen, 45147 Essen, Germany; and
| | - Henning Reis
- Medical School, University of Duisburg-Essen, 45147 Essen, Germany; and.,Institute of Pathology, University Hospital Essen, 45147 Essen, Germany
| | - Elke Cario
- Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, 45147 Essen, Germany; .,Medical School, University of Duisburg-Essen, 45147 Essen, Germany; and
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18
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Rangan P, Choi I, Wei M, Navarrete G, Guen E, Brandhorst S, Enyati N, Pasia G, Maesincee D, Ocon V, Abdulridha M, Longo VD. Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology. Cell Rep 2019; 26:2704-2719.e6. [PMID: 30840892 PMCID: PMC6528490 DOI: 10.1016/j.celrep.2019.02.019] [Citation(s) in RCA: 197] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/01/2019] [Accepted: 02/06/2019] [Indexed: 12/31/2022] Open
Abstract
Dietary interventions are potentially effective therapies for inflammatory bowel diseases (IBDs). We tested the effect of 4-day fasting-mimicking diet (FMD) cycles on a chronic dextran sodium sulfate (DSS)-induced murine model resulting in symptoms and pathology associated with IBD. These FMD cycles reduced intestinal inflammation, increased stem cell number, stimulated protective gut microbiota, and reversed intestinal pathology caused by DSS, whereas water-only fasting increased regenerative and reduced inflammatory markers without reversing pathology. Transplants of Lactobacillus or fecal microbiota from DSS- and FMD-treated mice reversed DSS-induced colon shortening, reduced inflammation, and increased colonic stem cells. In a clinical trial, three FMD cycles reduced markers associated with systemic inflammation. The effect of FMD cycles on microbiota composition, immune cell profile, intestinal stem cell levels and the reversal of pathology associated with IBD in mice, and the anti-inflammatory effects demonstrated in a clinical trial show promise for FMD cycles to ameliorate IBD-associated inflammation in humans.
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Affiliation(s)
- Priya Rangan
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Inyoung Choi
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Min Wei
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Gerardo Navarrete
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Esra Guen
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Sebastian Brandhorst
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Nobel Enyati
- USC Dornsife College of Letters, Arts & Sciences, Department of Biological Sciences, University of Southern California, 3551 Trousdale Pkwy, Los Angeles, CA 90089-0191, USA
| | - Gab Pasia
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Daral Maesincee
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Vanessa Ocon
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Maya Abdulridha
- Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA
| | - Valter D Longo
- USC Dornsife College of Letters, Arts & Sciences, Department of Biological Sciences, University of Southern California, 3551 Trousdale Pkwy, Los Angeles, CA 90089-0191, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, 1425 San Pablo St, Los Angeles, CA 90033, USA; IFOM FIRC Institute of Molecular Oncology, Via Adamello 16, Milano 20139, Italy.
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19
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Abstract
NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity. The C-terminal conserves a leucine-rich repeats (LRRs) domain which can modulate NLRP3 activity and sense endogenous alarmins and microbial ligands. In contrast, the N-terminal pyrin domain (PYD) can account for homotypic interactions with the adaptor protein-ASC of NLRP3 inflammasome. These characters enable it function in innate immunity. Its downstream effector proteins include caspase-1 and IL-1β etc. which exhibit protective or detrimental roles in mucosal immunity in different studies. Here, we comprehensively review the current literature regarding the physiology of NLRP3 inflammasome and its potential roles in the pathogenesis of IBD. We also discuss about the complex interactions among the NLRP3 inflammasome, mucosal immune response, and gut homeostasis as found in experimental models and IBD patients.
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Affiliation(s)
- Yu Zhen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- The Centre of Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- The Centre of Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
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20
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Wong J, Chopra J, Chiang LLW, Liu T, Ho J, Wu WKK, Tse G, Wong SH. The Role of Connexins in Gastrointestinal Diseases. J Mol Biol 2019; 431:643-652. [PMID: 30639409 DOI: 10.1016/j.jmb.2019.01.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/03/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022]
Abstract
Gap junctions are hexagonal arrays of protein molecules in the plasma membrane and were first described in Mauthner cell synapses of goldfish. They form pathways for coupling between cells, allowing passive, electrotonic spread of ions and also passage of larger molecules such as amino acids and nucleotides. They are expressed in both excitable and non-excitable tissues. Each gap junction is made of two connexons, which are hexameric proteins of the connexin subunit. In this review, the roles that connexins play in gastrointestinal motility, the mechanisms of altered connexin expression leading to inflammatory bowel disease, gastrointestinal infections, and gastrointestinal symptoms in autistic spectrum disorder are discussed in detail.
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Affiliation(s)
- Jeremy Wong
- Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, PR China
| | - Jasmine Chopra
- Faculty of Arts and Science, University of Toronto, Toronto, Canada
| | | | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, PR China
| | - Jeffery Ho
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, PR China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, PR China
| | - William K K Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, PR China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, PR China
| | - Gary Tse
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, PR China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, PR China.
| | - Sunny Hei Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, PR China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, PR China.
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21
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Intestinal microbiome adjusts the innate immune setpoint during colonization through negative regulation of MyD88. Nat Commun 2018; 9:4099. [PMID: 30291253 PMCID: PMC6173721 DOI: 10.1038/s41467-018-06658-4] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 09/17/2018] [Indexed: 11/17/2022] Open
Abstract
Host pathways mediating changes in immune states elicited by intestinal microbial colonization are incompletely characterized. Here we describe alterations of the host immune state induced by colonization of germ-free zebrafish larvae with an intestinal microbial community or single bacterial species. We show that microbiota-induced changes in intestinal leukocyte subsets and whole-body host gene expression are dependent on the innate immune adaptor gene myd88. Similar patterns of gene expression are elicited by colonization with conventional microbiome, as well as mono-colonization with two different zebrafish commensal bacterial strains. By studying loss-of-function myd88 mutants, we find that colonization suppresses Myd88 at the mRNA level. Tlr2 is essential for microbiota-induced effects on myd88 transcription and intestinal immune cell composition. It remains unclear how microbial sensing during early-life colonization results in immune homeostasis rather than acute inflammation. Here the authors show that zebrafish larvae colonization suppresses intestinal MyD88, accounting for a considerable proportion of microbiota-induced alterations in immune setpoint.
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22
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Beggs AD, James J, Caldwell G, Prout T, Dilworth MP, Taniere P, Iqbal T, Morton DG, Matthews G. Discovery and Validation of Methylation Biomarkers for Ulcerative Colitis Associated Neoplasia. Inflamm Bowel Dis 2018; 24:1503-1509. [PMID: 29762666 PMCID: PMC6176894 DOI: 10.1093/ibd/izy119] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Indexed: 12/11/2022]
Abstract
Background and aims Ulcerative colitis (UC) is associated with a higher background risk of dysplasia and/or neoplasia due to chronic inflammation. There exist few biomarkers for identification of patients with dysplasia, and targeted biopsies in this group of patients are inaccurate in reliably identifying dysplasia. We aimed to examine the epigenome of UC dysplasia and to identify and validate potential biomarkers. Methods Colonic samples from patients with UC-associated dysplasia or neoplasia underwent epigenome-wide analysis on the Illumina 450K methylation array. Markers were validated by bisulphite pyrosequencing on a secondary validation cohort and accuracy calculated using logistic regression and receiver-operator curves. Results Twelve samples from 4 patients underwent methylation array analysis and 6 markers (GNG7, VAV3, KIF5C, PIK3R5, TUBB6, and ZNF583) were taken forward for secondary validation on a cohort of 71 colonic biopsy samples consisting of normal uninflamed mucosa from control patients, acute and chronic colitis, "field" mucosa in patients with dysplasia/neoplasia, dysplasia, and neoplasia. Methylation in the beta-tubulin TUBB6 correlated with the presence of dysplasia (P < 0.0001) and accurately discriminated between dysplasia and nondysplastic tissue, even in the apparently normal field mucosa downstream from dysplastic lesions (AUC 0.84, 95% CI 0.81-0.87). Conclusions Methylation in TUBB6 is a potential biomarker for UC- associated dysplasia. Further validation is needed and is ongoing as part of the ENDCAP-C study.
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Affiliation(s)
- Andrew D Beggs
- Institute of Cancer and Genomic Science, University of Birmingham
| | - Jonathan James
- Institute of Cancer and Genomic Science, University of Birmingham
| | | | - Toby Prout
- Institute of Cancer and Genomic Science, University of Birmingham
| | - Mark P Dilworth
- Institute of Cancer and Genomic Science, University of Birmingham
| | - Phillipe Taniere
- Institute of Cancer and Genomic Science, University of Birmingham
| | - Tariq Iqbal
- Institute of Cancer and Genomic Science, University of Birmingham
| | - Dion G Morton
- Institute of Cancer and Genomic Science, University of Birmingham
| | - Glenn Matthews
- Institute of Cancer and Genomic Science, University of Birmingham
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23
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Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis. Pediatr Res 2018; 83:1031-1040. [PMID: 29360809 PMCID: PMC5959752 DOI: 10.1038/pr.2018.14] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 01/11/2018] [Indexed: 12/17/2022]
Abstract
BackgroundThere is substantial evidence that signaling through Toll-like receptor 4 (TLR4) contributes to the pathogenesis of necrotizing enterocolitis (NEC). Pregnane X receptor (PXR), a xenobiotic sensor and signaling intermediate for certain host-bacterial metabolites, has been shown to negatively regulate TLR4 signaling. Here we investigated the relationship between PXR and TLR4 in the developing murine intestine and explored the capacity of PXR to modulate inflammatory pathways involved in experimental NEC.MethodsWild-type and PXR-/- mice were studied at various time points of development in an experimental model of NEC. In addition, we studied the ability of the secondary bile acid lithocholic acid (LCA), a known PXR agonist in liver, to activate intestinal PXR and reduce NEC-related intestinal inflammation.ResultsWe found a reciprocal relationship between the developmental expression of PXR and TLR4 in wild-type murine intestine, with PXR acting to reduce TLR4 expression by decreasing TLR4 mRNA stability. In addition, PXR-/- mice exhibited a remarkably heightened severity of disease in experimental NEC. Moreover, LCA attenuated intestinal proinflammatory responses in the early stages of experimental NEC.ConclusionThese findings provide proactive insights into the regulation of TLR4 in the developing intestine. Targeting PXR may be a novel approach for NEC prevention.
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24
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Corridoni D, Chapman T, Ambrose T, Simmons A. Emerging Mechanisms of Innate Immunity and Their Translational Potential in Inflammatory Bowel Disease. Front Med (Lausanne) 2018. [PMID: 29515999 PMCID: PMC5825991 DOI: 10.3389/fmed.2018.00032] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Activation of the innate immune system through pattern-recognition receptor (PRR) signaling plays a pivotal role in the early induction of host defense following exposure to pathogens. Loss of intestinal innate immune regulation leading aberrant immune responses has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The precise role of PRRs in gut inflammation is not well understood, but considering their role as bacterial sensors and their genetic association with IBD, they likely contribute to dysregulated immune responses to the commensal microbiota. The purpose of this review is to evaluate the emerging functions of PRRs including their functional cross-talk, how they respond to mitochondrial damage, induce mitophagy or autophagy, and influence adaptive immune responses by interacting with the antigen presentation machinery. The review also summarizes some of the recent attempts to harness these pathways for therapeutic approaches in intestinal inflammation.
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Affiliation(s)
- Daniele Corridoni
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.,Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Thomas Chapman
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.,Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Tim Ambrose
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.,Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Alison Simmons
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.,Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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25
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Abstract
Pyroptosis is a kind of programmed cell death mediated by caspases-1/4/5/11. Pancreatic acinar cell death is the major pathophysiological change in early acute pancreatitis (AP), which is an important factor determining its progression and prognosis. Different ways of cell death affect AP progression differently. At present, most scholars believe that the increased proportion of apoptotic cells can mitigate AP, while necrosis has an opposite effect. In our early study, we used electron microscope to observe the morphology of acinar cells and found that there are many cells consistent with the characteristics of pyroptosis. The expression of caspase-1 was analyzed via immunohistochemical staining in acinar cells in AP, which suggests that pyroptosis may play a role in acinar cell death and inflammation. In this review, we review the recent findings regarding the occurrence and modulation of pyroptosis by caspase-1 and inflammsome, and in particular, discuss the potential mechanism and clinical significance of pyroptosis in AP, with an aim to provide new clues to the clinical diagnosis and therapy of this disease.
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Affiliation(s)
- Xiang-Ren Jin
- Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
| | - Xue-Wei Bai
- Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
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26
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Hennenberg EM, Eyking A, Reis H, Cario E. MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis. PLoS One 2017; 12:e0180834. [PMID: 28686677 PMCID: PMC5501609 DOI: 10.1371/journal.pone.0180834] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 06/21/2017] [Indexed: 12/13/2022] Open
Abstract
Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/deficiency
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/immunology
- Animals
- B-Lymphocytes/immunology
- B-Lymphocytes/pathology
- Carcinogenesis/genetics
- Carcinogenesis/immunology
- Carcinogenesis/pathology
- Chemotaxis
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/pathology
- Colorectal Neoplasms/complications
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/immunology
- Colorectal Neoplasms/pathology
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/immunology
- DNA-Binding Proteins/deficiency
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/immunology
- Disease Models, Animal
- Epiregulin/genetics
- Epiregulin/immunology
- Gene Expression Regulation, Neoplastic
- Genes, Immunoglobulin Light Chain/genetics
- Humans
- Interleukin-11/genetics
- Interleukin-11/immunology
- Intestinal Mucosa/immunology
- Intestinal Mucosa/pathology
- Leukocyte Common Antigens/genetics
- Leukocyte Common Antigens/immunology
- Male
- Mice
- Mice, Knockout
- Monocyte Chemoattractant Proteins/genetics
- Monocyte Chemoattractant Proteins/immunology
- Signal Transduction
- TNF-Related Apoptosis-Inducing Ligand/genetics
- TNF-Related Apoptosis-Inducing Ligand/immunology
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Affiliation(s)
- Eva Maria Hennenberg
- Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
- Medical School, University of Duisburg-Essen, Essen, Germany
| | - Annette Eyking
- Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
- Medical School, University of Duisburg-Essen, Essen, Germany
| | - Henning Reis
- Medical School, University of Duisburg-Essen, Essen, Germany
- Institute of Pathology, University Hospital Essen, Essen, Germany
| | - Elke Cario
- Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
- Medical School, University of Duisburg-Essen, Essen, Germany
- * E-mail:
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27
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Cario E. P-glycoprotein multidrug transporter in inflammatory bowel diseases: More questions than answers. World J Gastroenterol 2017; 23:1513-1520. [PMID: 28321153 PMCID: PMC5340804 DOI: 10.3748/wjg.v23.i9.1513] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 01/06/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in the intestinal microbiota composition, affect mucosal immune responses, disturb tissue integrity and impair regeneration. The multidrug transporter ABCB1/MDR1 p-glycoprotein (p-gp) plays a key role at the front line of host defence by efficiently protecting the gastrointestinal barrier from xenobiotic accumulation. This Editorial discusses how altered expression and function of ABCB1/MDR1 p-gp may contribute to the development and persistence of chronic intestinal inflammation in inflammatory bowel diseases (IBD). Recent evidence implies multiple interactions between intestinal microbiota, innate immunity and xenobiotic metabolism via p-gp. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1A develop spontaneously chronic colitis, providing a highly valuable murine IBD model for the study of intestinal epithelial barrier function, immunoregulation, infectious co-triggers and novel therapeutic approaches. Possible associations of human ABCB1 gene polymorphisms with IBD susceptibility have been evaluated, but results are inconsistent. Future studies must focus on further elucidation of the pathophysiological relevance and immunological functions of p-gp and how its ambiguous effects could be therapeutically targeted in IBD.
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28
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Choteau L, Vancraeyneste H, Le Roy D, Dubuquoy L, Romani L, Jouault T, Poulain D, Sendid B, Calandra T, Roger T, Jawhara S. Role of TLR1, TLR2 and TLR6 in the modulation of intestinal inflammation and Candida albicans elimination. Gut Pathog 2017; 9:9. [PMID: 28289440 PMCID: PMC5310049 DOI: 10.1186/s13099-017-0158-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 02/03/2017] [Indexed: 01/19/2023] Open
Abstract
Background Toll-like receptors (TLRs) are the major pattern recognition receptors that mediate sensing of a wide range of microorganisms. TLR2 forms heterodimers with either TLR1 or TLR6, broadening its ligand diversity against pathogens. TLR1, TLR2 and TLR6 have been implicated in the recognition of Candida albicans, an opportunistic fungal pathogen that colonizes the gastrointestinal tract. In this study, we explored whether the deficiency in TLR1, TLR2 or TLR6 impacts C. albicans colonization and inflammation-associated colonic injury in the dextran sulfate sodium (DSS)-induced colitis in mice. Results DSS treatment and C. albicans challenge induced greater weight loss, worse clinical signs of inflammation, higher histopathologic scores, and increased mortality rates in TLR1−/− and TLR2−/− mice when compared to TLR6−/− and wild-type mice. The number of C. albicans colonies in the stomach, colon and feces was decreased in TLR6−/− mice as compared to TLR2−/−, TLR1−/− and wild-type mice. Interestingly, the population of E. coli in colonic luminal contents, intestinal permeability to FITC-dextran and cytokine expression were significantly increased in TLR1−/− and TLR2−/− mice, while they were decreased in TLR6−/− mice. Conclusion In contrast to TLR6, both TLR1 and TLR2 deficiencies increased intestinal inflammation, and the overgrowth of C. albicans and E. coli populations in the colitis model, suggesting the involvement of TLR1 and TLR2 in epithelial homeostasis, and a role of TLR6 in increasing intestinal inflammation in response to pathogen-sensing. Electronic supplementary material The online version of this article (doi:10.1186/s13099-017-0158-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Laura Choteau
- INSERM U995/2, Université Lille Nord de France, 1 Place Verdun, 59000 Lille, France.,U995-LIRIC, Lille Inflammation Research International Center, University Lille2, 59000 Lille, France.,Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Hélène Vancraeyneste
- INSERM U995/2, Université Lille Nord de France, 1 Place Verdun, 59000 Lille, France.,U995-LIRIC, Lille Inflammation Research International Center, University Lille2, 59000 Lille, France.,Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Didier Le Roy
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Laurent Dubuquoy
- INSERM U995/2, Université Lille Nord de France, 1 Place Verdun, 59000 Lille, France.,U995-LIRIC, Lille Inflammation Research International Center, University Lille2, 59000 Lille, France
| | - Luiginia Romani
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
| | - Thierry Jouault
- INSERM U995/2, Université Lille Nord de France, 1 Place Verdun, 59000 Lille, France.,U995-LIRIC, Lille Inflammation Research International Center, University Lille2, 59000 Lille, France
| | - Daniel Poulain
- INSERM U995/2, Université Lille Nord de France, 1 Place Verdun, 59000 Lille, France.,U995-LIRIC, Lille Inflammation Research International Center, University Lille2, 59000 Lille, France.,Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Boualem Sendid
- INSERM U995/2, Université Lille Nord de France, 1 Place Verdun, 59000 Lille, France.,U995-LIRIC, Lille Inflammation Research International Center, University Lille2, 59000 Lille, France.,Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Thierry Calandra
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Samir Jawhara
- INSERM U995/2, Université Lille Nord de France, 1 Place Verdun, 59000 Lille, France.,U995-LIRIC, Lille Inflammation Research International Center, University Lille2, 59000 Lille, France.,Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
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29
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Emerging Roles for Epigenetic Programming in the Control of Inflammatory Signaling Integration in Heath and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1024:63-90. [PMID: 28921465 DOI: 10.1007/978-981-10-5987-2_3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Macrophages and dendritic cells initiate the innate immune response to infection and injury and contribute to inflammatory signaling to maintain the homeostasis of various tissues, which includes resident macrophages for the elimination of invading microorganisms and tissue damage. Inappropriate inflammatory signaling can lead to persistent inflammation and further develop into autoimmune and inflammation-associated diseases. Inflammatory signaling pathways have been well characterized, but how these signaling pathways are converted into sustained and diverse patterns of expression of cytokines, chemokines, and other genes in response to environmental challenges is unclear. Emerging evidence suggests the important role of epigenetic mechanisms in finely tuning the outcome of the host innate immune response. An understanding of epigenetic regulation of innate immune cell identity and function will enable the identification of the mechanism between gene-specific host defenses and inflammatory disease and will also allow for exploration of the program of innate immune memory in health and disease. This information could be used to develop therapeutic agents to enhance the host response, preventing chronic inflammation through preserving tissues and signaling integrity.
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30
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Inflammasomes in the Gut Mucosal Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1024:133-151. [PMID: 28921468 DOI: 10.1007/978-981-10-5987-2_6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammasomes are critical checkpoints in inflammation. The activation of inflammasome can cause a series of inflammatory responses including maturation of interleukin (IL)-1β and IL-18 and a specialized form of cell death called pyroptosis. Since its identification in the early 2000s, inflammasomes have been implicated to play multifaceted roles in varied pathological and physiological conditions, especially in the mucosal compartments including the gut. Maintaining gut mucosal homeostasis has always been a remarkable challenge for the host due to both the vast mucosal surface that is exposed to the outside and the enormous amount of local microbiota. To accomplish this challenge, the host mounts a constant dynamic low-grade inflammatory response (physiological inflammation) in coping with insults of microbes in the intestine. This book chapter aims to summarize the current knowledge of how inflammasomes contribute to gut mucosal homeostasis.
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31
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Tunis MC, Dawod B, Carson KR, Veinotte LL, Marshall JS. Toll-like receptor 2 activators modulate oral tolerance in mice. Clin Exp Allergy 2016; 45:1690-702. [PMID: 26242919 PMCID: PMC5019435 DOI: 10.1111/cea.12605] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 06/18/2015] [Accepted: 07/03/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND Toll-like receptor 2 (TLR2) is a widely expressed pattern recognition receptor critical for innate immunity. TLR2 is also a key regulator of mucosal immunity implicated in the development of allergic disease. TLR2 activators are found in many common foods, but the role of TLR2 in oral tolerance and allergic sensitization to foods is not well understood. OBJECTIVE The purpose of this study was to evaluate the impacts of TLR2 expression and TLR2 activation on oral tolerance to food antigens in a murine model. METHODS Mice were fed ovalbumin (OVA) or peanut butter with or without the addition of low doses of TLR2 activators Pam3 CSK4 or FSL-1. Oral tolerance was assessed by analysing antibody responses after a systemic antigen challenge. OVA-specific Tregs were assessed in the Peyer's patches, mesenteric lymph nodes, and spleen in wild-type and TLR2(-/-) mice. Low-dose Pam3 CSK4 was also tested as an oral adjuvant. RESULTS Oral tolerance was successfully induced in both wild-type and TLR2(-/-) recipient mice, with an associated regulatory T-cell response. Oral TLR2 activation, with low-dose Pam3 CSK4 or FSL-1, during oral antigen exposure was found to alter oral tolerance and was associated with the development of substantial IgE and IgA responses to foods upon systemic challenge. Low-dose oral Pam3 CSK4 treatment also selectively enhanced antigen-specific IgA responses to oral antigen exposure. CONCLUSIONS AND CLINICAL RELEVANCE TLR2 is not necessary for oral tolerance induction, but oral TLR2 activation modulates humoral IgE and IgA responses during tolerance development. Low-dose Pam3 CSK4 is also an effective oral adjuvant that selectively enhances IgA production. These observations are pertinent to the optimization of oral allergen immunotherapy and oral vaccine development.
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Affiliation(s)
- M C Tunis
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Dalhousie Inflammation Group, Dalhousie University, Halifax, NS, Canada
| | - B Dawod
- Dalhousie Inflammation Group, Dalhousie University, Halifax, NS, Canada.,Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - K R Carson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Dalhousie Inflammation Group, Dalhousie University, Halifax, NS, Canada
| | - L L Veinotte
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Dalhousie Inflammation Group, Dalhousie University, Halifax, NS, Canada
| | - J S Marshall
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Dalhousie Inflammation Group, Dalhousie University, Halifax, NS, Canada.,Department of Pathology, Dalhousie University, Halifax, NS, Canada
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32
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Souza-Fonseca-Guimaraes F, Krasnova Y, Putoczki T, Miles K, MacDonald KP, Town L, Shi W, Gobe GC, McDade L, Mielke LA, Tye H, Masters SL, Belz GT, Huntington ND, Radford-Smith G, Smyth MJ. Granzyme M has a critical role in providing innate immune protection in ulcerative colitis. Cell Death Dis 2016; 7:e2302. [PMID: 27441655 PMCID: PMC4973354 DOI: 10.1038/cddis.2016.215] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 06/03/2016] [Accepted: 06/06/2016] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel disease (IBD) is an immunoregulatory disorder, associated with a chronic and inappropriate mucosal immune response to commensal bacteria, underlying disease states such as ulcerative colitis (UC) and Crohn's disease (CD) in humans. Granzyme M (GrzM) is a serine protease expressed by cytotoxic lymphocytes, in particular natural killer (NK) cells. Granzymes are thought to be involved in triggering cell death in eukaryotic target cells; however, some evidence supports their role in inflammation. The role of GrzM in the innate immune response to mucosal inflammation has never been examined. Here, we discover that patients with UC, unlike patients with CD, display high levels of GrzM mRNA expression in the inflamed colon. By taking advantage of well-established models of experimental UC, we revealed that GrzM-deficient mice have greater levels of inflammatory indicators during dextran sulfate sodium (DSS)-induced IBD, including increased weight loss, greater colon length reduction and more severe intestinal histopathology. The absence of GrzM expression also had effects on gut permeability, tissue cytokine/chemokine dynamics, and neutrophil infiltration during disease. These findings demonstrate, for the first time, that GrzM has a critical role during early stages of inflammation in UC, and that in its absence colonic inflammation is enhanced.
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Affiliation(s)
- F Souza-Fonseca-Guimaraes
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria 3010, Australia.,Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - Y Krasnova
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.,School of Medicine, University of Queensland, St Lucia, Queensland 4006, Australia
| | - T Putoczki
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - K Miles
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - K P MacDonald
- Antigen Presentation and Immunoregulation Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - L Town
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - W Shi
- Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - G C Gobe
- Centre for Kidney Disease Research, School of Medicine, University of Queensland at Translational Research Institute, St Lucia, Queensland 4006, Australia
| | - L McDade
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - L A Mielke
- Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - H Tye
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - S L Masters
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - G T Belz
- Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - N D Huntington
- Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - G Radford-Smith
- Inflammatory Bowel Disease Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.,Department of Gastroenterology, Royal Brisbane and Women's Hospital, Herston, Queensland 4006, Australia
| | - M J Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.,School of Medicine, University of Queensland, St Lucia, Queensland 4006, Australia
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Toll-like receptors in the pathogenesis of chemotherapy-induced gastrointestinal toxicity. Curr Opin Support Palliat Care 2016; 10:157-64. [DOI: 10.1097/spc.0000000000000202] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Ignacio A, Morales CI, Câmara NOS, Almeida RR. Innate Sensing of the Gut Microbiota: Modulation of Inflammatory and Autoimmune Diseases. Front Immunol 2016; 7:54. [PMID: 26925061 PMCID: PMC4759259 DOI: 10.3389/fimmu.2016.00054] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 02/04/2016] [Indexed: 12/13/2022] Open
Abstract
The mammalian gastrointestinal tract harbors a diverse microbial community with which dynamic interactions have been established over millennia of coevolution. Commensal bacteria and their products are sensed by innate receptors expressed in gut epithelia and in gut-associated immune cells, thereby promoting the proper development of mucosal immune system and host homeostasis. Many studies have demonstrated that host–microbiota interactions play a key role during local and systemic immunity. Therefore, this review will focus on how innate sensing of the gut microbiota and their metabolites through inflammasome and toll-like receptors impact the modulation of a distinct set of inflammatory and autoimmune diseases. We believe that a better understanding of the fine-tuning that governs host–microbiota interactions will further improve common prophylactic and therapeutic applications.
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Affiliation(s)
- Aline Ignacio
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil
| | - Camila Ideli Morales
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Medicine, Nephrology Division, Federal University of São Paulo, São Paulo, Brazil; Renal Pathophysiology Laboratory, Department of Clinical Medicine, University of São Paulo, São Paulo, Brazil
| | - Rafael Ribeiro Almeida
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil
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35
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Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis. Mediators Inflamm 2015; 2015:250762. [PMID: 26483605 PMCID: PMC4592906 DOI: 10.1155/2015/250762] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 09/08/2015] [Indexed: 12/13/2022] Open
Abstract
Intestinal epithelial cells (IECs) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium.
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Intestinal neuroendocrine cells and goblet cells are mediators of IL-17A-amplified epithelial IL-17C production in human inflammatory bowel disease. Mucosal Immunol 2015; 8:943-58. [PMID: 25492478 DOI: 10.1038/mi.2014.124] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 10/30/2014] [Indexed: 02/04/2023]
Abstract
Interleukin (IL)-17C is a novel member of the IL-17 cytokine family. Its function in human inflammatory bowel disease (IBD) remains elusive as its role in colonic inflammation is entirely derived from murine models. We aimed to analyze the role of IL-17C in human IBD, focusing on T helper type 17 (Th17) cell- and intestinal epithelial cell (IEC)-dependent mechanisms. IL-17C mRNA (P=0.005), serum levels (P=0.008), and colonic staining intensity (P=0.004) is increased in active IBD. Serum IL-17C levels are modified by IL23R genotypes and IL-17C mRNA correlates (r>0.5, P<0.001) with IL-17A, tumor necrosis factor (TNF)-α, C-C motif chemokine ligand 20 (CCL20) and IL-23 mRNA in the inflamed colon of IBD patients. In the inflamed colon, IL-17C is produced by enteroendocrine and goblet cells, with contrary polar cytosolic localization of IL-17C within the cellular axis. In these two cell types, IL-17A strongly amplifies TNF-α-induced IL-17C production. On the molecular level, IL-17C production in IECs is dependent on TNF-α-activated nuclear factor-κB, extracellular signal-regulated kinase-1/2 and p38, and IL-17A-activated Akt, monocyte chemotactic protein-induced protein 1, and C/EBPδ. IL-17C upregulates the Th17 chemoattractant CCL20 in IECs. In summary, our findings support the involvement of IL-17A-amplified IL-17C production by enteroendocrine and goblet cells in the pathogenesis of active IBD, revealing an interaction between the neuroendocrine system and the Th17 pathway in human IBD.
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Zhang W, Zhu YH, Yang JC, Yang GY, Zhou D, Wang JF. A Selected Lactobacillus rhamnosus Strain Promotes EGFR-Independent Akt Activation in an Enterotoxigenic Escherichia coli K88-Infected IPEC-J2 Cell Model. PLoS One 2015; 10:e0125717. [PMID: 25915861 PMCID: PMC4411159 DOI: 10.1371/journal.pone.0125717] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 03/17/2015] [Indexed: 12/24/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) are important intestinal pathogens that cause diarrhea in humans and animals. Although probiotic bacteria may protect against ETEC-induced enteric infections, the underlying mechanisms are unknown. In this study, porcine intestinal epithelial J2 cells (IPEC-J2) were pre-incubated with and without Lactobacillus rhamnosus ATCC 7469 and then exposed to F4+ ETEC. Increases in TLR4 and NOD2 mRNA expression were observed at 3 h after F4+ ETEC challenge, but these increases were attenuated by L. rhamnosus treatment. Expression of TLR2 and NOD1 mRNA was up-regulated in cells pre-treated with L. rhamnosus. Pre-treatment with L. rhamnosus counteracted F4+ ETEC-induced increases in TNF-α concentration. Increased PGE2. concentrations were observed in cells infected with F4+ ETEC and in cells treated with L. rhamnosus only. A decrease in phosphorylated epidermal growth factor receptor (EGFR) was observed at 3 h after F4+ ETEC challenge in cells treated with L. rhamnosus. Pre-treatment with L. rhamnosus enhanced Akt phosphorylation and increased ZO-1 and occludin protein expression. Our findings suggest that L. rhamnosus protects intestinal epithelial cells from F4+ ETEC-induced damage, partly through the anti-inflammatory response involving synergism between TLR2 and NOD1. In addition, L. rhamnosus promotes EGFR-independent Akt activation, which may activate intestinal epithelial cells in response to bacterial infection, in turn increasing tight junction integrity and thus enhancing the barrier function and restricting pathogen invasion. Pre-incubation with L. rhamnosus was superior to co-incubation in reducing the adhesion of F4+ ETEC to IPEC-J2 cells and subsequently attenuating F4+ ETEC-induced mucin layer destruction and suppressing apoptosis. Our data indicate that a selected L. rhamnosus strain interacts with porcine intestinal epithelial cells to maintain the epithelial barrier and promote intestinal epithelial cell activation in response to bacterial infection, thus protecting cells from the deleterious effects of F4+ ETEC.
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Affiliation(s)
- Wei Zhang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yao-Hong Zhu
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jin-Cai Yang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Gui-Yan Yang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Dong Zhou
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jiu-Feng Wang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, Beijing, China
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Nguyen V, Pearson K, Kim JH, Kamdar K, DePaolo RW. Retinoic acid can exacerbate T cell intrinsic TLR2 activation to promote tolerance. PLoS One 2015; 10:e0118875. [PMID: 25826367 PMCID: PMC4380421 DOI: 10.1371/journal.pone.0118875] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 01/13/2015] [Indexed: 01/15/2023] Open
Abstract
The contribution of vitamin A to immune health has been well established. However, recent evidence indicates that its active metabolite, retinoic acid (RA), has the ability to promote both tolerogenic and inflammatory responses. While the outcome of RA-mediated immunity is dependent upon the immunological status of the tissue, the contribution of specific innate signals influencing this response have yet to be delineated. Here, we found that treatment with RA can dampen inflammation during intestinal injury. Importantly, we report a novel and unexpected requirement for TLR2 in RA-mediated suppression. Our data demonstrate that RA treatment enhances TLR2-dependent IL-10 production from T cells and this, in turn, potentiates T regulatory cell (TREG) generation without the need for activation of antigen presenting cells. These data also suggest that combinatorial therapy using RA and TLR2 ligands may be advantageous in the design of therapies to treat autoimmune or inflammatory disease.
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Affiliation(s)
- Vivien Nguyen
- Department of Pediatric Gastroenterology and Nutrition, Children’s Hospital of Los Angeles, Los Angeles, California, United States of America
| | - Kandyce Pearson
- Department of Molecular Microbiology and Immunology, Keck School of Medicine and University of Southern California, Los Angeles, California, United States of America
| | - Jee-Hyun Kim
- Department of Molecular Microbiology and Immunology, Keck School of Medicine and University of Southern California, Los Angeles, California, United States of America
| | - Karishma Kamdar
- Department of Molecular Microbiology and Immunology, Keck School of Medicine and University of Southern California, Los Angeles, California, United States of America
| | - R. William DePaolo
- Department of Molecular Microbiology and Immunology, Keck School of Medicine and University of Southern California, Los Angeles, California, United States of America
- * E-mail:
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Frank M, Hennenberg EM, Eyking A, Rünzi M, Gerken G, Scott P, Parkhill J, Walker AW, Cario E. TLR signaling modulates side effects of anticancer therapy in the small intestine. THE JOURNAL OF IMMUNOLOGY 2015; 194:1983-95. [PMID: 25589072 DOI: 10.4049/jimmunol.1402481] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Intestinal mucositis represents the most common complication of intensive chemotherapy, which has a severe adverse impact on quality of life of cancer patients. However, the precise pathophysiology remains to be clarified, and there is so far no successful therapeutic intervention. In this study, we investigated the role of innate immunity through TLR signaling in modulating genotoxic chemotherapy-induced small intestinal injury in vitro and in vivo. Genetic deletion of TLR2, but not MD-2, in mice resulted in severe chemotherapy-induced intestinal mucositis in the proximal jejunum with villous atrophy, accumulation of damaged DNA, CD11b(+)-myeloid cell infiltration, and significant gene alterations in xenobiotic metabolism, including a decrease in ABCB1/multidrug resistance (MDR)1 p-glycoprotein (p-gp) expression. Functionally, stimulation of TLR2 induced synthesis and drug efflux activity of ABCB1/MDR1 p-gp in murine and human CD11b(+)-myeloid cells, thus inhibiting chemotherapy-mediated cytotoxicity. Conversely, TLR2 activation failed to protect small intestinal tissues genetically deficient in MDR1A against DNA-damaging drug-induced apoptosis. Gut microbiota depletion by antibiotics led to increased susceptibility to chemotherapy-induced mucosal injury in wild-type mice, which was suppressed by administration of a TLR2 ligand, preserving ABCB1/MDR1 p-gp expression. Findings were confirmed in a preclinical model of human chemotherapy-induced intestinal mucositis using duodenal biopsies by demonstrating that TLR2 activation limited the toxic-inflammatory reaction and maintained assembly of the drug transporter p-gp. In conclusion, this study identifies a novel molecular link between innate immunity and xenobiotic metabolism. TLR2 acts as a central regulator of xenobiotic defense via the multidrug transporter ABCB1/MDR1 p-gp. Targeting TLR2 may represent a novel therapeutic approach in chemotherapy-induced intestinal mucositis.
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Affiliation(s)
- Magdalena Frank
- Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany
| | - Eva Maria Hennenberg
- Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany
| | - Annette Eyking
- Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany
| | - Michael Rünzi
- Medical School, University of Duisburg-Essen, D-45122 Essen, Germany; Division of Gastroenterology and Metabolic Diseases, Kliniken Essen Süd, D-45239 Essen, Germany
| | - Guido Gerken
- Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany
| | - Paul Scott
- Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; and
| | - Julian Parkhill
- Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; and
| | - Alan W Walker
- Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; and Microbiology Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB21 9SB, United Kingdom
| | - Elke Cario
- Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany;
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41
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Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassamy S. TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. THE JOURNAL OF IMMUNOLOGY 2014; 193:4203-13. [PMID: 25210120 DOI: 10.4049/jimmunol.1400614] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the β-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.
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Affiliation(s)
- Indumathi Manoharan
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Yuan Hong
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Amol Suryawanshi
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | | | - Zuoming Sun
- Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010
| | - Andrew L Mellor
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and
| | - David H Munn
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Santhakumar Manicassamy
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and
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Huang E, Wells CA. The ground state of innate immune responsiveness is determined at the interface of genetic, epigenetic, and environmental influences. THE JOURNAL OF IMMUNOLOGY 2014; 193:13-9. [PMID: 24951823 DOI: 10.4049/jimmunol.1303410] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Monocytes and macrophages form the major cellular component of the innate immune system, with roles in tissue development, homeostasis, and host defense against infection. Environmental factors were shown to play a significant part in determining innate immune responsiveness, and this included systemic conditions, such as circulating glucose levels, gut microflora, time of year, and even diurnal rhythm, which had a direct impact on innate immune receptor expression. Although the underlying molecular processes are just beginning to emerge, it is clear that environmental factors may alter epigenetic states of peripheral blood monocytes and resident tissue macrophages. We conclude that some measure of cellular ground state must become an essential part of the analysis of myeloid responsiveness or infectious susceptibility.
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Affiliation(s)
- Edward Huang
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia; and
| | - Christine Anne Wells
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia; and Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom
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43
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Parlato M, Yeretssian G. NOD-like receptors in intestinal homeostasis and epithelial tissue repair. Int J Mol Sci 2014; 15:9594-627. [PMID: 24886810 PMCID: PMC4100112 DOI: 10.3390/ijms15069594] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 05/16/2014] [Accepted: 05/20/2014] [Indexed: 12/13/2022] Open
Abstract
The intestinal epithelium constitutes a dynamic physical barrier segregating the luminal content from the underlying mucosal tissue. Following injury, the epithelial integrity is restored by rapid migration of intestinal epithelial cells (IECs) across the denuded area in a process known as wound healing. Hence, through a sequence of events involving restitution, proliferation and differentiation of IECs the gap is resealed and homeostasis reestablished. Relapsing damage followed by healing of the inflamed mucosa is a hallmark of several intestinal disorders including inflammatory bowel diseases (IBD). While several regulatory peptides, growth factors and cytokines stimulate restitution of the epithelial layer after injury, recent evidence in the field underscores the contribution of innate immunity in controlling this process. In particular, nucleotide-binding and oligomerization domain-like receptors (NLRs) play critical roles in sensing the commensal microbiota, maintaining homeostasis, and regulating intestinal inflammation. Here, we review the process of intestinal epithelial tissue repair and we specifically focus on the impact of NLR-mediated signaling mechanisms involved in governing epithelial wound healing during disease.
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Affiliation(s)
- Marianna Parlato
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Garabet Yeretssian
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Abstract
Intestinal epithelial cells were once thought to be inert, non-responsive cells that simply acted as a physical barrier that prevents the contents of the intestinal lumen from accessing the underlying tissue. However, it is now clear that these cells express a full repertoire of Toll- and Nod-like receptors, and that their activation by components of the microbiota is vital for the development of a functional epithelium, maintenance of barrier integrity, and defense against pathogenic organisms. Additionally, mounting evidence suggests that epithelial sensing of bacteria plays a significant role in the management of the numbers and types of microbes present in the gut microbiota via the production of antimicrobial peptides and other microbe-modulatory products. This is a critical process, as it is now becoming apparent that alterations in the composition of the microbiota can predispose an individual to a wide variety of chronic diseases. In this review, we will discuss the bacterial pattern recognition receptors that are known to be expressed by the intestinal epithelium, and how each of them individually contributes to these vital protective functions. Moreover, we will review what is known about the communication between epithelial cells and various classes of underlying leukocytes, and discuss how they interact with the microbiota to form a three-part relationship that maintains homeostasis in the gut.
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45
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Lin N, Xu LF, Sun M. The protective effect of trefoil factor 3 on the intestinal tight junction barrier is mediated by toll-like receptor 2 via a PI3K/Akt dependent mechanism. Biochem Biophys Res Commun 2013; 440:143-149. [PMID: 24051092 DOI: 10.1016/j.bbrc.2013.09.049] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 09/09/2013] [Indexed: 01/29/2023]
Abstract
Trefoil factor peptides are highly conserved secreted molecules characterized by heat and enzymatic digestion resistance. Intestinal trefoil factor 3 (TFF3) protects and repairs the gastrointestinal mucosa and restores normal intestinal permeability, which is dependent on the integrity of the tight junction (TJ) barrier and the TJ associated proteins claudin-1, zona occludens-1 (ZO-1) and occludin. Despite the important role of intestinal barrier dysfunction in the pathogenesis of inflammatory bowel diseases, the underlying mechanisms and associated molecules remain unclear. In the present study, we show that TFF3 and toll-like receptor 2 (TLR2) are functionally linked and modulate intestinal epithelial permeability via a mechanism that involves the PI3K/Akt pathway. We used the Caco-2 cell model to show that TLR2 and TFF3 inhibit the IL-1β induced increase in permeability and release of proinflammatory cytokines, and that this effect is mediated by activation of PI3K/Akt signaling. TLR2 silencing downregulated the expression of TFF3 and overexpression of TLR2 and TFF3 increased the levels of phospho-Akt. TFF3 overexpression significantly upregulated the expression of ZO-1, occludin and claudin-1 and this effect was abrogated by inhibition of the PI3K/Akt pathway. Taken together, our results indicate that TLR2 signaling selectively enhances intestinal TJ barrier integrity through a mechanism involving TFF3 and the activation of the PI3K/Akt pathway.
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Affiliation(s)
- Nan Lin
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
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