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Wang H, Ma L, Su W, Liu Y, Xie N, Liu J. NLRP3 inflammasome in health and disease (Review). Int J Mol Med 2025; 55:48. [PMID: 39930811 PMCID: PMC11781521 DOI: 10.3892/ijmm.2025.5489] [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: 09/19/2024] [Accepted: 12/16/2024] [Indexed: 02/13/2025] Open
Abstract
Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.
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Affiliation(s)
- Haoran Wang
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Li Ma
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Weiran Su
- Department of Internal Medicine, Jiading District Central Hospital, Shanghai 201800, P.R. China
| | - Yangruoyu Liu
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Ning Xie
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Jun Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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Liu X, Li D, Zhang Y, Liu H, Chen P, Zhao Y, Ruscitti P, Zhao W, Dong G. Identifying Common Genetic Etiologies Between Inflammatory Bowel Disease and Related Immune-Mediated Diseases. Biomedicines 2024; 12:2562. [PMID: 39595128 PMCID: PMC11592296 DOI: 10.3390/biomedicines12112562] [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: 09/12/2024] [Revised: 10/25/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) have an increased risk of developing immune-mediated diseases. However, the genetic basis of IBD is complex, and an integrated approach should be used to elucidate the complex genetic relationship between IBD and immune-mediated diseases. METHODS The genetic relationship between IBD and 16 immune-mediated diseases was examined using linkage disequilibrium score regression. GWAS data were synthesized from two IBD databases using the METAL, and multi-trait analysis of genome-wide association studies was performed to enhance statistical robustness and identify novel genetic associations. Independent risk loci were meticulously examined using conditional and joint genome-wide multi-trait analysis, multi-marker analysis of genomic annotation, and functional mapping and annotation of significant genetic loci, integrating the information of quantitative trait loci and different methodologies to identify risk-related genes and proteins. RESULTS The results revealed four immune-mediated diseases (AS, psoriasis, iridocyclitis, and PsA) with a significant relationship with IBD. The multi-trait analysis revealed 909 gene loci of statistical significance. Of these loci, 28 genetic variants were closely related to IBD, and 7 single-nucleotide polymorphisms represented novel independent risk loci. In addition, 14 genes and 514 proteins were found to be associated with susceptibility to immune-mediated diseases. Notably, IL1RL1 emerged as a key player, present within pleiotropic genes across multiple protein databases, highlighting its potential as a therapeutic target. CONCLUSIONS This study suggests that the common polygenic determinants between IBD and immune-mediated diseases are widely distributed across the genome. The findings not only support a shared genetic relationship between IBD and immune-mediated diseases but also provide novel therapeutic targets for these diseases.
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Affiliation(s)
- Xianqiang Liu
- Medical School of Chinese PLA, Beijing 100853, China; (X.L.)
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
| | - Dingchang Li
- Medical School of Chinese PLA, Beijing 100853, China; (X.L.)
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
| | - Yue Zhang
- Medical School of Chinese PLA, Beijing 100853, China; (X.L.)
| | - Hao Liu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Peng Chen
- Medical School of Chinese PLA, Beijing 100853, China; (X.L.)
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
| | - Yingjie Zhao
- Medical School of Chinese PLA, Beijing 100853, China; (X.L.)
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
| | - Piero Ruscitti
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Wen Zhao
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Guanglong Dong
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
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Wang P, Tang CT, Li J, Huang X, Jin R, Yin F, Liu Z, Chen Y, Zeng C. The E3 ubiquitin ligase RNF31 mediates the development of ulcerative colitis by regulating NLRP3 inflammasome activation. Int Immunopharmacol 2023; 125:111194. [PMID: 37951199 DOI: 10.1016/j.intimp.2023.111194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 11/04/2023] [Accepted: 11/05/2023] [Indexed: 11/13/2023]
Abstract
Ulcerative colitis (UC) is characterized by dysregulated inflammation and disruption of the intestinal barrier. The NLRP3 inflammasome, which is composed of NLRP3, ASC, and caspase-1, plays a crucial role in UC pathogenesis by triggering the production of proinflammatory cytokines. In this study, we investigated the regulatory role of RNF31 in NLRP3 inflammasome activation during UC development. Through comprehensive analysis of ulcerative colitis tissues using the GEO database and immunohistochemistry, we found that RNF31 expression was elevated in UC tissues, which prompted further investigation into its function. We constructed an RNF31 knockdown cell model and observed a significant reduction in NLRP3 inflammasome activation, indicating the involvement of RNF31 in regulating NLRP3. Mechanistically, RNF31 could interact with NLRP3 through the RBR structural domain, leading to increased K63-linked ubiquitination of NLRP3 and consequent stabilization. Coimmunoprecipitation experiments revealed a mutual interaction between RNF31 and NLRP3, substantiating their functional association. Finally, an in vivo mouse model with RNF31 knockdown showed a notable reduction in NLRP3 expression, which was accompanied by a decrease in the proinflammatory cytokines IL-18 and IL-1β. The successful attenuation of DSS-induced tissue inflammation by this treatment confirmed the physiological relevance of RNF31-mediated regulation of NLRP3. This study unveils a novel regulatory pathway by which RNF31 affects NLRP3 inflammasome activation, providing new insights into UC pathogenesis and potential therapeutic targets for UC treatment.
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Affiliation(s)
- Peng Wang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chao-Tao Tang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi, China
| | - Jun Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xia Huang
- The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ruiri Jin
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fang Yin
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zide Liu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Youxiang Chen
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi, China
| | - Chunyan Zeng
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi, China.
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Hou M, Leng Y, Shi Y, Tan Z, Min X. Astragalus membranaceus as a Drug Candidate for Inflammatory Bowel Disease: The Preclinical Evidence. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2023; 51:1501-1526. [PMID: 37530507 DOI: 10.1142/s0192415x23500684] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that include Crohn's disease (CD) and ulcerative colitis (UC). Today, IBD has no successful treatment. As a result, it is of paramount importance to develop novel therapeutic agents for IBD prevention and treatment. Astragalus membranaceus (AMS) is a traditional Chinese medicine found in the AMS root. Modern pharmacological studies indicate that AMS and its constituents exhibit multiple bioactivities, such as anti-inflammatory, anti-oxidant, immune regulatory, anticancer, hypolipidemic, hypoglycemic, hepatoprotective, expectorant, and diuretic effects. AMS and its active constituents, which have been reported to be effective in IBD treatment, are believed to be viable candidate drugs for IBD treatment. These underlying mechanisms are associated with anti-inflammation, anti-oxidation, immunomodulation, intestinal epithelial repair, gut microbiota homeostasis, and improved energy metabolism. In this review, we summarize the efficacy and underlying mechanisms involved in IBD treatment with AMS and its active constituents in preclinical studies.
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Affiliation(s)
- Min Hou
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China
| | - Yufang Leng
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China
- Department of Anesthesiology, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China
| | - Yajing Shi
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China
| | - Zhiguo Tan
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China
| | - Xiangzhen Min
- Department of Anesthesiology, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China
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Levy E, Marcil V, Tagharist Ép Baumel S, Dahan N, Delvin E, Spahis S. Lactoferrin, Osteopontin and Lactoferrin–Osteopontin Complex: A Critical Look on Their Role in Perinatal Period and Cardiometabolic Disorders. Nutrients 2023; 15:nu15061394. [PMID: 36986124 PMCID: PMC10052990 DOI: 10.3390/nu15061394] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023] Open
Abstract
Milk-derived bioactive proteins have increasingly gained attention and consideration throughout the world due to their high-quality amino acids and multiple health-promoting attributes. Apparently, being at the forefront of functional foods, these bioactive proteins are also suggested as potential alternatives for the management of various complex diseases. In this review, we will focus on lactoferrin (LF) and osteopontin (OPN), two multifunctional dairy proteins, as well as to their naturally occurring bioactive LF–OPN complex. While describing their wide variety of physiological, biochemical, and nutritional functionalities, we will emphasize their specific roles in the perinatal period. Afterwards, we will evaluate their ability to control oxidative stress, inflammation, gut mucosal barrier, and intestinal microbiota in link with cardiometabolic disorders (CMD) (obesity, insulin resistance, dyslipidemia, and hypertension) and associated complications (diabetes and atherosclerosis). This review will not only attempt to highlight the mechanisms of action, but it will critically discuss the potential therapeutic applications of the underlined bioactive proteins in CMD.
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Affiliation(s)
- Emile Levy
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Valérie Marcil
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Sarah Tagharist Ép Baumel
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Noam Dahan
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
| | - Edgard Delvin
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Biochemistry &Molecular Medicine, Faculty of Medicine, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Schohraya Spahis
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Biochemistry &Molecular Medicine, Faculty of Medicine, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
- Correspondence: ; Tel.: +1-(514)-345-4832
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Li W, Lückstädt W, Wöhner B, Bub S, Schulz A, Socher E, Arnold P. Structural and functional properties of meprin β metalloproteinase with regard to cell signaling. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119136. [PMID: 34626678 DOI: 10.1016/j.bbamcr.2021.119136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/05/2021] [Accepted: 09/06/2021] [Indexed: 10/20/2022]
Abstract
The metalloproteinase meprin β plays an important role during collagen I deposition in the skin, mucus detachment in the small intestine and also regulates the abundance of different cell surface proteins such as the interleukin-6 receptor (IL-6R), the triggering receptor expressed on myeloid cells 2 (TREM2), the cluster of differentiation 99 (CD99), the amyloid precursor protein (APP) and the cluster of differentiation 109 (CD109). With that, regulatory mechanisms that control meprin β activity and regulate its release from the cell surface to enable access to distant substrates are increasingly important. Here, we will summarize factors that alternate meprin β activity and thereby regulate its proteolytic activity on the cell surface or in the supernatant. We will also discuss cleavage of the IL-6R and TREM2 on the cell surface and compare it to CD109. CD109, as a substrate of meprin β, is cleaved within the protein core, thereby releasing defined fragments from the cell surface. At last, we will also summarize the role of proteases in general and meprin β in particular in substrate release on extracellular vesicles.
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Affiliation(s)
- Wenjia Li
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Wiebke Lückstädt
- Institute of Anatomy, Christian-Albrechts-Universität zu Kiel (CAU), Kiel, Germany
| | - Birte Wöhner
- Institute of Anatomy, Christian-Albrechts-Universität zu Kiel (CAU), Kiel, Germany
| | - Simon Bub
- Department of Molecular-Neurology, University Hospital Erlangen, Erlangen, Germany
| | - Antonia Schulz
- Institute of Anatomy, Christian-Albrechts-Universität zu Kiel (CAU), Kiel, Germany
| | - Eileen Socher
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Philipp Arnold
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
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Keshavarz Shahbaz S, Koushki K, Ayati SH, Bland AR, Bezsonov EE, Sahebkar A. Inflammasomes and Colorectal Cancer. Cells 2021; 10:2172. [PMID: 34571825 PMCID: PMC8467678 DOI: 10.3390/cells10092172] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/22/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammasomes are important intracellular multiprotein signaling complexes that modulate the activation of caspase-1 and induce levels of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to pathogenic microorganisms and molecules that originated from host proteins. Inflammasomes play contradictory roles in the development of inflammation-induced cancers. Based on several findings, inflammasomes can initiate and promote carcinogenesis. On the contrary, inflammasomes also exhibit anticancer effects by triggering pyroptosis and immunoregulatory functions. Herein, we review extant studies delving into different functions of inflammasomes in colorectal cancer development.
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Affiliation(s)
- Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Science, Qazvin 3419759811, Iran;
| | - Khadijeh Koushki
- Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran;
| | - Seyed Hassan Ayati
- Immunobiochemistry Lab, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran;
| | - Abigail R. Bland
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand;
| | - Evgeny E. Bezsonov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia;
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 1313199137, Iran
- School of Medicine, The University of Western Australia, Perth 6009, Australia
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
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Tan G, Huang C, Chen J, Chen B, Zhi F. Gasdermin-E-mediated pyroptosis participates in the pathogenesis of Crohn's disease by promoting intestinal inflammation. Cell Rep 2021; 35:109265. [PMID: 34133932 DOI: 10.1016/j.celrep.2021.109265] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 11/01/2020] [Accepted: 05/26/2021] [Indexed: 11/23/2022] Open
Abstract
Crohn's disease (CD) is a kind of refractory intestinal inflammatory diseases. Pyroptosis was recently identified as a gasdermin-mediated proinflammatory cell death. However, it is unclear whether gasdermin-mediated pyroptosis participates in the pathogenesis of CD. Here, we show that the pyroptosis-inducing fragment GSDME N-terminal is obviously detected in the inflamed colonic mucosa but not in the uninflamed mucosa of patients with CD, suggesting that GSDME-mediated pyroptosis may be correlated with intestinal mucosal inflammation in CD. To investigate the role of GSDME in colitis development, Gsdme-/- mice and wild-type (WT) littermate controls were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis. We found that Gsdme-/- mice exhibit less-severe intestinal inflammation than WT controls do. Furthermore, our results indicate that GSDME-mediated epithelial-cell pyroptosis induces intestinal inflammation through the release of proinflammatory intracellular contents. In summary, we show that GSDME participates in the pathogenesis of CD through GSDME-mediated pyroptosis to release proinflammatory cytokines.
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Affiliation(s)
- Gao Tan
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Chongyang Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiaye Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bingxia Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Fachao Zhi
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Azlan A, Salamonsen LA, Hutchison J, Evans J. Endometrial inflammasome activation accompanies menstruation and may have implications for systemic inflammatory events of the menstrual cycle. Hum Reprod 2021; 35:1363-1376. [PMID: 32488243 DOI: 10.1093/humrep/deaa065] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 02/28/2020] [Indexed: 12/14/2022] Open
Abstract
STUDY QUESTION Does NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation within decidualized endometrial stromal cells accompany menstruation and is this reflected systemically? SUMMARY ANSWER Components of the NLRP3 inflammasome immunolocalize to decidualized endometrial stromal cells immediately prior to menstruation, and are activated in an in vitro model of menstruation, as evidenced by downstream interleukin (IL)-1beta and IL-18 release, this being reflected systemically in vivo. WHAT IS KNOWN ALREADY Menstruation is a highly inflammatory event associated with activation of NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), local release of chemokines and cytokines and inflammatory leukocyte influx. Systemically, chemokines and cytokines fluctuate across the menstrual cycle. STUDY DESIGN, SIZE, DURATION This study examined the NLRP3 inflammasome and activation of downstream IL-1beta and IL-18 in endometrial tissues from women of known fertility (≥1 previous parous pregnancy) across the menstrual cycle (n ≥ 8 per cycle phase), serum from women during the proliferative, secretory and menstrual phases (≥9 per cycle phase) of the cycle and menstrual fluid collected on Day 2 of menses (n = 18). Endometrial stromal cells isolated from endometrial tissue biopsies (n = 10 in total) were used for an in vitro model of pre-menstrual hormone withdrawal. PARTICIPANTS/MATERIALS, SETTING, METHODS Expression and localization of components of the NLRP3 inflammasome (NLRP3 & apoptosis-associated speck-caspase recruit domain [ASC]) in endometrial tissues was performed by immunohistochemistry. Unbiased digital quantification of immunohistochemical staining allowed determination of different patterns of expression across the menstrual cycle. Serum from women across the menstrual cycle was examined for IL-1beta and IL-18 concentrations by ELISA. An in vitro model of hormone withdrawal from estrogen/progestin decidualized endometrial stromal cells was used to more carefully examine activation of the NLRP3 inflammasome. Endometrial stromal cells isolated from endometrial tissue biopsies (n = 10) were treated with estrogen/medroxyprogesterone acetate for 12 days to induce decidualization (assessed by release of prolactin) followed by withdrawal of steroid hormone support. Activation of NLRP3, & ASC in these cells was examined on Days 0-3 after hormone withdrawal by Western immunoblotting. Release of IL-1beta and IL-18 examined during decidualization and across the same time course of hormone withdrawal by ELISA. Specific involvement of NLRP3 inflammasome activation in IL-1beta and IL-18 release after hormone withdrawal was investigated via application of the NLRP3 inflammasome inhibitor MCC950 at the time of hormone withdrawal. MAIN RESULTS AND THE ROLE OF CHANCE Critical components of the NLRP3 inflammasome (NLRP3, ASC) were increased in menstrual phase endometrial tissues versus early secretory phase tissues (P < 0.05, n/s, respectively). NLRP3 and ASC were also elevated in the proliferative versus secretory phase of the cycle (P < 0.01, n/s, respectively) with ASC also significantly increased in the late-secretory versus early-secretory phase (P < 0.05). The pattern of activation was reflected in systemic levels of the inflammasome mediators, with IL-1beta and IL-18 elevated in peripheral blood serum during menstruation (Day 2 of menses) versus secretory phase (P = 0.026, P = 0.0042, respectively) and significantly elevated in menstrual fluid (Day 2 of menses) versus systemic levels across all cycle phases, suggesting that local inflammasome activation within the endometrium during menses is reflected by systemic inflammation. NLRP3 and ASC localized to decidualized cells adjacent to the spiral arterioles in the late secretory phase of the menstrual cycle, where the menstrual cascade is thought to be initiated, and to endometrial leukocytes during the menstrual phase. NLRP3 also localized to glandular epithelial cells during the late-secretory/menstrual phases. Localization of both NLRP3 and ASC switched from predominant epithelial localization during the early-secretory phase to stromal localization during the late-secretory/menstrual phase. Using an in vitro model of hormone withdrawal from decidualized human endometrial stromal cells, we demonstrated progressive activation of NLRP3 and ASC after hormone withdrawal increasing from Day 0 of withdrawal/Day 12 of decidualization to Day 3 of withdrawal. Downstream release of IL-1beta and IL-18 from decidualized stromal cells after hormone withdrawal followed the same pattern with the role of NLRP3 inflammasome activation confirmed via the inhibition of IL-1beta and IL-18 release upon application of MCC950. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION This study uses descriptive and semi-quantitative measures of NLRP3 inflammasome activation within endometrial tissues. Further, the in vitro model of pre-menstrual hormone withdrawal may not accurately recapitulate the in vivo environment as only one cell type is present and medroxyprogesterone acetate replaced natural progesterone due to its longer stability. WIDER IMPLICATIONS OF THE FINDINGS We provide novel evidence that the NLRP3 inflammasome is activated within decidualized endometrial stromal cells immediately prior to menses and that local activation of the inflammasome within the endometrium appears to be reflected systemically in by activation of downstream IL-1beta and IL-18. Given the prevalence of menstrual disorders associated with inflammation including dysmenorrhoea and aspects of pre-menstrual syndrome, the inflammasome could be a novel target for ameliorating such burdens. STUDY FUNDING/COMPETING INTEREST(S) The authors have no competing interests. J.E. was supported by a Fielding Foundation fellowship, NHMRC project grants (#1139489 and #1141946) and The Hudson Institute of Medical Research. L.A.S. was supported by The Hudson Institute of Medical Research and J.H. by an Australian Government Research Training Program Scholarship. We acknowledge the Victorian Government's Operating Infrastructure funding to the Hudson Institute. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Aida Azlan
- Centre for Reproductive Health, The Hudson Institute of Medical Research, 27-31 Wright Street, Clayton 3168, Australia.,Department of Physiology, Monash University, Clayton, 3800 VIC, Australia
| | - Lois A Salamonsen
- Centre for Reproductive Health, The Hudson Institute of Medical Research, 27-31 Wright Street, Clayton 3168, Australia.,Department of Molecular and Translational Medicine, Monash University, Clayton 3800 VIC, Australia
| | - Jennifer Hutchison
- Centre for Reproductive Health, The Hudson Institute of Medical Research, 27-31 Wright Street, Clayton 3168, Australia.,Department of Molecular and Translational Medicine, Monash University, Clayton 3800 VIC, Australia
| | - Jemma Evans
- Centre for Reproductive Health, The Hudson Institute of Medical Research, 27-31 Wright Street, Clayton 3168, Australia.,Department of Molecular and Translational Medicine, Monash University, Clayton 3800 VIC, Australia
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10
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Privitera G, Pugliese D, Lopetuso LR, Scaldaferri F, Neri M, Guidi L, Gasbarrini A, Armuzzi A. Novel trends with biologics in inflammatory bowel disease: sequential and combined approaches. Therap Adv Gastroenterol 2021; 14:17562848211006669. [PMID: 33995579 PMCID: PMC8082976 DOI: 10.1177/17562848211006669] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/11/2021] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) management has changed dramatically over the past 20 years, after the introduction of targeted biological therapies. However, the impact of these new drugs in changing the natural history of disease is still under debate. Recent evidence seems to suggest that the extent of their efficacy might be, at least partially, dependent on the timing of their introduction and on the subsequent management strategy. In this complex landscape, the potential role for a more dynamic approach with treatments based on sequencing and combining targeted therapies has been explored only minimally so far. In this review, we aim to explore the potential biological rationale behind the use of sequential and combination therapies in IBD, to summarise the current knowledge on this topic and to propose a management algorithm that combines these notions.
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Affiliation(s)
- Giuseppe Privitera
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Daniela Pugliese
- CEMAD – IBD UNIT – Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome, Italy
| | - Loris Riccardo Lopetuso
- CEMAD – IBD UNIT – Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome, Italy,Department of Medicine and Ageing Sciences, ‘G. d’Annunzio’ University of Chieti-Pescara, Chieti, Italy,Center for Advanced Studies and Technology (CAST), ‘G. d’Annunzio’ University of Chieti-Pescara, Chieti, Italy
| | - Franco Scaldaferri
- CEMAD – IBD UNIT – Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome, Italy
| | - Matteo Neri
- Department of Medicine and Ageing Sciences, ‘G. d’Annunzio’ University of Chieti-Pescara, Chieti, Italy,Center for Advanced Studies and Technology (CAST), ‘G. d’Annunzio’ University of Chieti-Pescara, Chieti, Italy
| | - Luisa Guidi
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy,CEMAD – IBD UNIT – Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy,CEMAD – IBD UNIT – Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome, Italy
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11
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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: 24] [Impact Index Per Article: 4.8] [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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12
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Sabzevary-Ghahfarokhi M, Soltani A, Luzza F, Larussa T, Rahimian G, Shirzad H, Bagheri N. The protective effects of resveratrol on ulcerative colitis via changing the profile of Nrf2 and IL-1β protein. Mol Biol Rep 2020; 47:6941-6947. [PMID: 32888128 DOI: 10.1007/s11033-020-05753-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/28/2020] [Indexed: 11/26/2022]
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with increasing incidence and prevalence in developed countries. The presence of inflammatory cytokines is considered the main detrimental factor in severe types of IBD. The Nrf2 transcription factor plays an important role in reducing the expression of inflammatory agents such as interleukin (IL)-1β and increasing reparative factors such as IL-11. Resveratrol, a plant-derived phenolic compound, reduces the damage in chronic experimentally induced colitis. Twenty patients with UC and also 20 healthy controls were recruited in this study. The proteins expression of Nrf2 and IL-1β was assessed in colonic biopsies by Western blotting. Caco-2 cells were challenged with TNF-α (in vitro simulation of UC), in the presence or not of 190 nM (24 h) and 75 nM (48 h) Resveratrol. Then, Nrf2 and IL-1β in gene and protein expression were measured by real time-PCR and Western blotting in different treatments. Finally, IL-11 proteins expression was measured in culture supernatant by ELISA. A significant increase of IL-1β protein was detected in inflamed colonic tissues from UC patients compared with the control individuals. In Caco-2 cells challenged with TNF-α, protein expression of IL-1β and p-Nrf2 showed an increase, while gene expression of Nrf2 did not show a significant difference. After treatment with Resveratrol, both IL-1β mRNA and protein levels were reduced, while IL-11 protein levels showed any increase. The p-Nrf2 is a dominant form which is prevalent in inflamed tissues from UC patients. Resveratrol can reverse the inflammatory effects of TNF-α by reducing IL-1β and increasing IL-11 production.
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Affiliation(s)
- Milad Sabzevary-Ghahfarokhi
- Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Amin Soltani
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Francesco Luzza
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100, Catanzaro, Italy
| | - Tiziana Larussa
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100, Catanzaro, Italy
| | - Ghorbanali Rahimian
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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13
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Mukherjee S, Kumar R, Tsakem Lenou E, Basrur V, Kontoyiannis DL, Ioakeimidis F, Mosialos G, Theiss AL, Flavell RA, Venuprasad K. Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation. Nat Immunol 2020; 21:626-635. [PMID: 32424362 DOI: 10.1038/s41590-020-0681-x] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 04/06/2020] [Indexed: 02/08/2023]
Abstract
The inflammasome NLRP6 plays a crucial role in regulating inflammation and host defense against microorganisms in the intestine. However, the molecular mechanisms by which NLRP6 function is inhibited to prevent excessive inflammation remain unclear. Here, we demonstrate that the deubiquitinase Cyld prevents excessive interleukin 18 (IL-18) production in the colonic mucosa by deubiquitinating NLRP6. We show that deubiquitination inhibited the NLRP6-ASC inflammasome complex and regulated the maturation of IL-18. Cyld deficiency in mice resulted in elevated levels of active IL-18 and severe colonic inflammation following Citrobacter rodentium infection. Further, in patients with ulcerative colitis, the concentration of active IL-18 was inversely correlated with CYLD expression. Thus, we have identified a novel regulatory mechanism that inhibits the NLRP6-IL-18 pathway in intestinal inflammation.
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Affiliation(s)
- Sandip Mukherjee
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.,Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Ritesh Kumar
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.,Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Elviche Tsakem Lenou
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.,Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Dimitris L Kontoyiannis
- School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.,Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Fotis Ioakeimidis
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - George Mosialos
- School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Arianne L Theiss
- Division of Gastroenterology and Hepatology, School of Medicine at the Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
| | - Richard A Flavell
- Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
| | - K Venuprasad
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. .,Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
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14
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Justino PFC, Franco AX, Pontier-Bres R, Monteiro CES, Barbosa ALR, Souza MHLP, Czerucka D, Soares PMG. Modulation of 5-fluorouracil activation of toll-like/MyD88/NF-κB/MAPK pathway by Saccharomyces boulardii CNCM I-745 probiotic. Cytokine 2019; 125:154791. [PMID: 31401369 DOI: 10.1016/j.cyto.2019.154791] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIM Chemotherapy drugs that act via Toll-like receptors (TLRs) can exacerbate mucosal injury through the production of cytokines. Intestinal mucositis can activate TLR2 and TLR4, resulting in the activation of NF-κB. Intestinal mucositis characterized by intense inflammation is the main side effect associated with 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii CNCM I-745 (S.b) is a probiotic yeast used in the treatment of gastrointestinal disorders. The main objective of the study was to evaluate the effect of S.b treatment on the Toll-like/MyD88/NF-κB/MAPK pathway activated during intestinal mucositis and in Caco-2 cells treated with 5-FU. METHODS The mice were divided into three groups: saline (control), saline + 5-FU, and 5-FU + S.b (1.6 × 1010 colony forming units/kg). After 3 days of S.b administration by gavage, the mice were euthanized and the jejunum and ileum were removed. In vitro, Caco2 cells were treated with 5-FU (1 mM) alone or in the presence of lipopolysaccharide (1 ng/ml). When indicated, cells were exposed to S.b. The jejunum/ileum samples and Caco2 cells were examined for the expression or concentration of the inflammatory components. RESULTS Treatment with S.b modulated the expressions of TLR2, TLR4, MyD88, NF-κB, ERK1/2, phospho-p38, phospho-JNK, TNF-α, IL-1β, and CXCL-1 in the jejunum/ileum and Caco2 cells following treatment with 5-FU. CONCLUSION Toll-like/MyD88/NF-κB/MAPK pathway are activated during intestinal mucositis and their modulation by S.b suggests a novel and valuable therapeutic strategy for intestinal inflammation.
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Affiliation(s)
- Priscilla F C Justino
- LEFFAG - Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Alvaro X Franco
- LEFFAG - Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - Carlos E S Monteiro
- LEFFAG - Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - André L R Barbosa
- LAFFEX - Laboratory of Experimental Physiopharmacology, Biotechnology and Biodiversity Center Research, Federal University of Piauí, Parnaíba, Brazil
| | - Marcellus H L P Souza
- LEFFAG - Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Dorota Czerucka
- Centre Scientifique de Monaco, 8 quai Antoine 1er, MC98000, Monaco
| | - Pedro M G Soares
- LEFFAG - Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Morphology, Medical School, Federal University of Ceara, Rua Delmiro de Farias s/n, Rodolfo Teofilo, Fortaleza, Ceara, Brazil.
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15
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Assessment of bioactivities of the human milk lactoferrin–osteopontin complex in vitro. J Nutr Biochem 2019; 69:10-18. [DOI: 10.1016/j.jnutbio.2019.03.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/28/2019] [Accepted: 03/14/2019] [Indexed: 02/02/2023]
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16
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Pu Z, Che Y, Zhang W, Sun H, Meng T, Xie H, Cao L, Hao H. Dual roles of IL-18 in colitis through regulation of the function and quantity of goblet cells. Int J Mol Med 2019; 43:2291-2302. [PMID: 31017261 PMCID: PMC6488178 DOI: 10.3892/ijmm.2019.4156] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 03/13/2019] [Indexed: 01/30/2023] Open
Abstract
The main aim of the present study was to investigate the dual roles and mechanism of interleukin (IL)‑18 in dextran sulfate sodium (DSS)‑induced colitis. Firstly, meta‑analysis was used to explore whether the levels of IL‑18 were different in patients with colon cancer or inflammatory bowel disease. The results demonstrated that IL‑18 (rs187238, ‑137G/C) increased the incidence rate of colon cancer in patients, while IL‑18 (rs187238, ‑137G/C) decreased the incidence rate of ulcerative colitis or Crohn's disease in patients. Therefore, IL‑18 (rs187238, ‑137G/C) may have a dual function in colitis. Next, the functional role of IL‑18 in colitis was further investigated, by use of a DSS‑induced colitis mouse model. Pre‑treatment of the mice with IL‑18 increased body weight, augmented colon length, reduced inflammatory infiltration, promoted mucin (Muc)‑2 expression, increased the function and quantity of goblet cells and increased the mRNA levels of resistin‑like molecule (RELM) β and trefoil factor family (TFF) 3 in mice with DSS‑induced colitis, through the IL‑22/STAT3 pathway. By contrast, treatment with IL‑18 at later stages of the disease reduced body weight, decreased colon length, enhanced inflammatory infiltration and reduced Muc‑2 expression, decreased the function and quantity of goblet cells and inhibited the mRNA levels of RELMβ and TFF3 in mice with DSS‑induced colitis. In conclusion, IL‑18 served a dual function in colitis by regulating the function of goblet cells. The anti‑inflammatory effects of IL‑18 were observed in the early stage of colitis‑induced inflammation, while the pro‑inflammatory effects were observed in the later stages of the disease.
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Affiliation(s)
- Zhichen Pu
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009
- Department of Clinical Pharmacy, Yijishan Hospital of Wannan Medical College, Anhui Provincial Center for Drug Clinical Evaluation, Wuhu, Anhui 241001
| | - Yuan Che
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009
| | - Weiwei Zhang
- Department of Pharmacy, Fourth People's Hospital of Maanshan, Maanshan, Anhui 243031, P.R. China
| | - Hui Sun
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009
| | - Tuo Meng
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009
| | - Haitang Xie
- Department of Clinical Pharmacy, Yijishan Hospital of Wannan Medical College, Anhui Provincial Center for Drug Clinical Evaluation, Wuhu, Anhui 241001
| | - Lijuan Cao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009
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17
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Dong G, Wang F, Xu L, Zhu M, Zhang B, Wang B. Serum interleukin-18: A novel prognostic indicator for acute respiratory distress syndrome. Medicine (Baltimore) 2019; 98:e15529. [PMID: 31124933 PMCID: PMC6571250 DOI: 10.1097/md.0000000000015529] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The aim of this study is to determine the biological function of serum interleukin-18 (IL-18) on prognosis in acute respiratory distress syndrome (ARDS).From October 2016 to September 2017, 150 patients with ARDS in the ICU were enrolled according to the Berlin 2012 definition. The enzyme-linked immunosorbent assay (ELISA) was used to detect the expression level of IL-18 in serum isolated from the patients. Patients were divided into survival group (82 cases) and non-survival group (68 cases) and followed up for at least 2 months. The serum IL-18 expression level on the prognosis was calculated by receiver operating characteristic curve (ROC).The expression level of serum IL-18 was significantly higher in the non-survival group than that in the survival group (P < .05). Based on the ROC curve, the sensitivity and specificity of IL-18 as a predictor of prognosis at a cutoff of 509.5 pg/mL were 88% and 82%, respectively, and the area under the curve (RUC) was 0.84 (P < .05).The expression level of serum IL-18 could be used to evaluate the possible outcomes of patients with ARDS.
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18
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NLRP3 inflammasome in colitis and colitis-associated colorectal cancer. Mamm Genome 2018; 29:817-830. [DOI: 10.1007/s00335-018-9783-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 09/04/2018] [Indexed: 12/21/2022]
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19
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Sabzevary-Ghahfarokhi M, Shohan M, Shirzad H, Rahimian G, Bagheri N, Soltani A, Deris F, Ghatreh-Samani M, Razmara E. The expression analysis of Fra-1 gene and IL-11 protein in Iranian patients with ulcerative colitis. BMC Immunol 2018; 19:17. [PMID: 29914371 PMCID: PMC6006762 DOI: 10.1186/s12865-018-0257-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 06/11/2018] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Fra-1 (fosl1) belongs to the activator protein1 (AP-1) family inducing IL-11 expression in oxidative stress condition. IL-11 plays a pivotal role in protecting epithelial barriers integrity. In this study, we investigated the Fra-1 gene expression in the inflamed mucosa of patients with ulcerative colitis (UC) as well as its relation to IL-11 expression. MATERIALS AND METHODS We enrolled 20 patients and 20 healthy controls with definite UC based on the clinical criteria. Fra-1 gene expression in inflamed and non-inflamed colonic biopsies was determined by real-time polymerase chain reaction (RT-PCR). The IL-11 protein concentration was measured by Enzyme-Linked Immunosorbent Assay (ELISA) method. Pearson correlation was applied to calculate the relation between Fra-1 and IL-11. RESULTS An increased level of Fra-1 gene expression was observed in patients with mild ulcerative colitis. The protein concentration of IL-11 was also increased in mild UC patients. Conversely, a significant decrease of IL-11 protein level was detected in severe UC patients compared to control group. CONCLUSION Oxidative stress in inflamed intestinal biopsies can induce fra-1 gene expression. Our findings suggest that Fra-1 transcription factor leads to the production of IL-11 protein in UC patients.
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Affiliation(s)
- Milad Sabzevary-Ghahfarokhi
- Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mojtaba Shohan
- Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Ghorbanali Rahimian
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Nader Bagheri
- Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Amin Soltani
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fatemeh Deris
- Department of Epidemiology and Biostatistics, School of Health, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahdi Ghatreh-Samani
- Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Ehsan Razmara
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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20
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Mak'Anyengo R, Duewell P, Reichl C, Hörth C, Lehr HA, Fischer S, Clavel T, Denk G, Hohenester S, Kobold S, Endres S, Schnurr M, Bauer C. Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut. JCI Insight 2018. [PMID: 29515025 DOI: 10.1172/jci.insight.96322] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Inflammatory bowel disease (IBD) is associated with enhanced levels of the IL-1 family cytokines IL-1β and IL-18, which are activated by the Nlrp3 inflammasome. Here, we investigated the role of inflammasome-driven cytokine release on T cell polarization and DC differentiation in steady state and T cell transfer colitis. In vitro and in vivo data showed that IL-1β induces Th17 polarization and increases GM‑CSF production by T cells. Reduced IL-1β levels in Nlrp3-/- mice correlated with enhanced FLT3L levels and increased frequency of tolerogenic CD103+ DC. In the T cell transfer colitis model, Nlrp3 deficiency resulted in lower IL‑1β levels, reduced Th17 immunity, and less severe colitis. Unaltered IL-18 levels in both mouse strains pointed toward Nlrp3-independent processing. Importantly, cohousing revealed that the gut microbiome had no impact on the observed Nlrp3-/- phenotype. This study demonstrates that NLRP3 acts as a molecular switch of intestinal homeostasis by shifting local immune cells toward an inflammatory phenotype via IL-1β.
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Affiliation(s)
- Rachel Mak'Anyengo
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Peter Duewell
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Cornelia Reichl
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Christine Hörth
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Hans-Anton Lehr
- Institute of Pathology, Medizin Campus Bodensee, Friedrichshafen, Germany
| | - Sandra Fischer
- Core Facility Microbiome, ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany
| | - Thomas Clavel
- Core Facility Microbiome, ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany.,Institute of Medical Microbiology, RWTH University Hospital, Aachen, Germany
| | - Gerald Denk
- Medizinische Klinik und Poliklinik II, Klinikum der Universität München, Munich, Germany
| | - Simon Hohenester
- Medizinische Klinik und Poliklinik II, Klinikum der Universität München, Munich, Germany
| | - Sebastian Kobold
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Stefan Endres
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Max Schnurr
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Christian Bauer
- Division of Gastroenterology, Endocrinology, Infectiology and Metabolism, University Hospital Giessen and Marburg, Campus Marburg, Philipps University Marburg, Marburg, Germany
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Yu SX, Chen W, Liu ZZ, Zhou FH, Yan SQ, Hu GQ, Qin XX, Zhang J, Ma K, Du CT, Gu JM, Deng XM, Han WY, Yang YJ. Non-Hematopoietic MLKL Protects Against Salmonella Mucosal Infection by Enhancing Inflammasome Activation. Front Immunol 2018; 9:119. [PMID: 29456533 PMCID: PMC5801401 DOI: 10.3389/fimmu.2018.00119] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/15/2018] [Indexed: 12/21/2022] Open
Abstract
The intestinal mucosal barrier is critical for host defense against pathogens infection. Here, we demonstrate that the mixed lineage kinase-like protein (MLKL), a necroptosis effector, promotes intestinal epithelial barrier function by enhancing inflammasome activation. MLKL−/− mice were more susceptible to Salmonella infection compared with wild-type counterparts, with higher mortality rates, increased body weight loss, exacerbated intestinal inflammation, more bacterial colonization, and severe epithelial barrier disruption. MLKL deficiency promoted early epithelial colonization of Salmonella prior to developing apparent intestinal pathology. Active MLKL was predominantly expressed in crypt epithelial cells, and experiments using bone marrow chimeras found that the protective effects of MLKL were dependent on its expression in non-hematopoietic cells. Intestinal mucosa of MLKL−/− mice had impaired caspase-1 and gasdermin D cleavages and decreased interleukin (IL)-18 release. Moreover, administration of exogenous recombinant IL-18 rescued the phenotype of increased bacterial colonization in MLKL−/− mice. Thus, our results uncover the role of MLKL in enhancing inflammasome activation in intestinal epithelial cells to inhibit early bacterial colonization.
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Affiliation(s)
- Shui-Xing Yu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wei Chen
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhen-Zhen Liu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Feng-Hua Zhou
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Shi-Qing Yan
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Gui-Qiu Hu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xiao-Xia Qin
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jie Zhang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ke Ma
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Chong-Tao Du
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jing-Min Gu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xu-Ming Deng
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wen-Yu Han
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yong-Jun Yang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
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The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res 2017; 60:201-218. [PMID: 28336424 DOI: 10.1016/j.preteyeres.2017.03.002] [Citation(s) in RCA: 547] [Impact Index Per Article: 68.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/13/2017] [Accepted: 03/14/2017] [Indexed: 02/07/2023]
Abstract
The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.
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Pellegrini C, Antonioli L, Lopez-Castejon G, Blandizzi C, Fornai M. Canonical and Non-Canonical Activation of NLRP3 Inflammasome at the Crossroad between Immune Tolerance and Intestinal Inflammation. Front Immunol 2017; 8:36. [PMID: 28179906 PMCID: PMC5263152 DOI: 10.3389/fimmu.2017.00036] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 01/09/2017] [Indexed: 12/16/2022] Open
Abstract
Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in regulating the integrity of intestinal homeostasis and shaping innate immune responses during bowel inflammation. Intensive research efforts are being made to achieve an integrated view about the protective/detrimental role of canonical and non-canonical NLRP3 inflammasome activation in the maintenance of intestinal microenvironment integrity. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome could represent a promising molecular target for the therapeutic management of inflammatory immune-mediated gut diseases. The present review has been intended to provide a critical appraisal of the available knowledge about the role of canonical and non-canonical NLRP3 inflammasome activation in the dynamic interplay between microbiota, intestinal epithelium, and innate immune system, taken together as a whole integrated network regulating the maintenance/breakdown of intestinal homeostasis. Moreover, special attention has been paid to the pharmacological modulation of NLRP3 inflammasome, emphasizing the concept that this multiprotein complex could represent a suitable target for the management of inflammatory bowel diseases.
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Affiliation(s)
- Carolina Pellegrini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, UK
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy
| | - Gloria Lopez-Castejon
- Manchester Collaborative Centre for Inflammation Research, University of Manchester , Manchester , UK
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy
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Abstract
PURPOSE OF REVIEW Cytokines of the intestinal microenvironment largely dictate immunological responses after mucosal insults and the dominance of homeostatic or proinflammatory pathways. This review presents important recent studies on the role of specific cytokines in the pathogenesis of intestinal inflammation. RECENT FINDINGS The particular mucosal effects of cytokines depend on their inherent properties but also the cellular origin, type of stimulatory antigens, intermolecular interactions, and the particular immunological milieu. Novel cytokines of the interleukin-1 (IL-1) family, including IL-33 and IL-36, have dominant roles in mucosal immunity, whereas more established ones such as IL-18 are constantly enriched with unique properties. Th17 cells are important mucosal constituents, although their profound plasticity, makes the specific set of cytokines they secrete more important than their mere numbers. Finally, various cytokines, such as tumor necrosis factor-α, IL-6, tumor necrosis factor-like cytokine 1A, and death receptor, 3 demonstrate dichotomous roles with mucosa-protective function in acute injury but proinflammatory effects during chronic inflammation. SUMMARY The role of cytokines in mucosal health and disease is increasingly revealed. Such information not only will advance our understanding of the pathogenesis of gut inflammation, but also set the background for development of reliable diagnostic and prognostic biomarkers and cytokine-specific therapies.
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Affiliation(s)
- Giorgos Bamias
- aAcademic Department of Gastroenterology, Kapodistrian University of Athens, Laikon Hospital, Athens, Greece bDivision of Gastrointestinal and Liver Disease, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA
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Wu H, Li XM, Wang JR, Gan WJ, Jiang FQ, Liu Y, Zhang XD, He XS, Zhao YY, Lu XX, Guo YB, Zhang XK, Li JM. NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR-IL-1R signalling axis. J Pathol 2015; 238:457-69. [PMID: 26564988 DOI: 10.1002/path.4670] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 11/02/2015] [Accepted: 11/06/2015] [Indexed: 01/05/2023]
Abstract
Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD.
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Affiliation(s)
- Hua Wu
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
| | - Xiu-Ming Li
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
| | - Jing-Ru Wang
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
| | - Wen-Juan Gan
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.,First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Fu-Quan Jiang
- School of Pharmaceutical Sciences, Xiamen University, People's Republic of China
| | - Yao Liu
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
| | - Xin-Dao Zhang
- School of Pharmaceutical Sciences, Xiamen University, People's Republic of China
| | - Xiao-Shun He
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
| | - Yuan-Yuan Zhao
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
| | - Xing-Xing Lu
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
| | - Yan-Bing Guo
- School of Pharmaceutical Sciences, Xiamen University, People's Republic of China.,Sanford-Burnham Medical Research Institute, Cancer Center, La Jolla, CA, USA
| | - Xiao-Kun Zhang
- School of Pharmaceutical Sciences, Xiamen University, People's Republic of China.,Sanford-Burnham Medical Research Institute, Cancer Center, La Jolla, CA, USA
| | - Jian-Ming Li
- Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China
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Voronov E, Apte RN. IL-1 in Colon Inflammation, Colon Carcinogenesis and Invasiveness of Colon Cancer. CANCER MICROENVIRONMENT : OFFICIAL JOURNAL OF THE INTERNATIONAL CANCER MICROENVIRONMENT SOCIETY 2015; 8:187-200. [PMID: 26686225 PMCID: PMC4715003 DOI: 10.1007/s12307-015-0177-7] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 12/07/2015] [Indexed: 12/12/2022]
Abstract
Interleukin-1 (IL-1) is a major "alarm" upstream pro-inflammatory cytokine that mainly acts by inducing cascades of cytokine and inflammation-promoting mediators. In the tumor arena, IL-1 is produced by both malignant and microenvironmental cells. IL-1α and IL-1β are the major agonists of IL-1, while IL-1Ra is a physiological inhibitor of pre-formed IL-1. IL-1α and IL-1β differ in their compartmentalization and in the producing cells. IL-1β is only active in its inflammasome dependent processed and secreted form and has been considered as the major mediator of inflammation. On the other hand, IL-1α is mainly cell-associated in tissue resident cells, being also active in its precursor form. The role of the IL-1 molecules in the unique microenvironment in the colon is largely unknown. Here, we described the role of IL-1α and IL-1β in colon homeostasis, colon inflammation, colon carcinogenesis and invasiveness of colorectal cancer. Understanding of the integrative role of IL-1α and IL-1β in these processes will facilitate the application of novel IL-1 modulating approaches.
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Affiliation(s)
- Elena Voronov
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Ron N Apte
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
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Wong DVT, Lima-Júnior RCP, Carvalho CBM, Borges VF, Wanderley CWS, Bem AXC, Leite CAVG, Teixeira MA, Batista GLP, Silva RL, Cunha TM, Brito GAC, Almeida PRC, Cunha FQ, Ribeiro RA. The Adaptor Protein Myd88 Is a Key Signaling Molecule in the Pathogenesis of Irinotecan-Induced Intestinal Mucositis. PLoS One 2015; 10:e0139985. [PMID: 26440613 PMCID: PMC4595146 DOI: 10.1371/journal.pone.0139985] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 09/21/2015] [Indexed: 01/03/2023] Open
Abstract
Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL–1 and IL–18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL–1β (405%), IL–18 (365%), COX–2 (2,777%) and NF-κB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL–18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis.
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Affiliation(s)
- Deysi V. T. Wong
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
- Laboratory of Molecular Biology, Department of Pathology, Cancer Institute of Ceará, Fortaleza, Brazil
| | - Roberto C. P. Lima-Júnior
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Cibele B. M. Carvalho
- Department of Pathology and Forensic Medicine, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Vanessa F. Borges
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Carlos W. S. Wanderley
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Amanda X. C. Bem
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Caio A. V. G. Leite
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Maraiza A. Teixeira
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Gabriela L. P. Batista
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Rangel L. Silva
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Thiago M. Cunha
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Gerly A. C. Brito
- Department of Morphology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Paulo R. C. Almeida
- Department of Pathology and Forensic Medicine, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
| | - Fernando Q. Cunha
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Ronaldo A. Ribeiro
- Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine–Federal University of Ceará, Fortaleza, Brazil
- Department of Clinical Oncology, Cancer Institute of Ceará, Fortaleza, Brazil
- * E-mail: ;
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Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. J Nutr Biochem 2015; 26:651-60. [PMID: 25762527 DOI: 10.1016/j.jnutbio.2015.01.002] [Citation(s) in RCA: 338] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 11/25/2014] [Accepted: 01/07/2015] [Indexed: 12/17/2022]
Abstract
Diet-induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability, and when they reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans-resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high-fat sucrose diet (HFS) and, in turn, improve gut health. Wistar rats were randomised into four groups fed an HFS diet supplemented or not with trans-resveratrol [15 mg/kg body weight (BW)/day], quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans-resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet-induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS-diet-induced gut microbiota dysbiosis. In contrast, trans-resveratrol supplementation alone or in combination with quercetin scarcely modified the profile of gut bacteria but acted at the intestinal level, altering the mRNA expression of tight-junction proteins and inflammation-associated genes.
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Abstract
BACKGROUND/AIMS Five million people currently live with Crohn's disease (CD) or ulcerative colitis, the two major forms of inflammatory bowel disease. Available treatments frequently result in side effects that compromise the immune health of the patient. Consequently, alternative therapies that cause fewer systemic effects are needed. Dioctahedral smectite clays have been utilized to treat medical conditions, including diarrheal and enteric disease. Herein, we report the ability of a refined dioctahedral smectite (NovaSil, NS) to sorb inflammatory proteins and reduce inflammation in a TNBS (2,4,6-trinitrobenzenesulfonic acid) mouse model of CD. We also investigated whether NS could rescue gut microbial diversity in TNBS-induced mice. METHODS ELISA, X-ray diffraction, and transmission electron microscopy were employed to characterize the NS-cytokine interaction in vitro. A TNBS mouse colitis model was utilized to study the efficacy of NS supplementation for 4 weeks. The three treatment groups included control, TNBS, and TNBS + NS. DNA was extracted from feces and sorted for bacterial phylogenetic analysis. RESULTS Results suggest that NS binds TNFα in vitro. In TNBS-treated mice, supplementation with NS significantly reduced weight loss, and serum proinflammatory cytokine levels (IL-2, IL-6, and IL-12, TNFα, IFNγ) compared with the TNBS group. TNBS-treated mice demonstrated a significant reduction in gut microbiota species richness when compared with the TNBS + NS group and control group. CONCLUSIONS NovaSil mitigated the effects of TNBS-induced colitis based on reduction in systemic markers of inflammation, significant improvement in weight gain, and intestinal microbial profile.
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Abstract
The understanding of the intestinal inflammation occurring in the inflammatory bowel diseases (IBD) has been immeasurably advanced by the development of the now numerous murine models of intestinal inflammation. The usefulness of this research tool in IBD studies has been enabled by our improved knowledge of mucosal immunity and thus our improved ability to interpret the complex responses of mice with various causes of colitis; in addition, it has been powered by the availability of models in which the mice have specific genetic and/or immunologic defects that can be related to the origin of the inflammation. Finally, and more recently, it has been enhanced by our newly acquired ability to define the intestinal microbiome under various conditions and thus to understand how intestinal microorganisms impact on inflammation. In this brief review of murine models of intestinal inflammation we focus mainly on the most often used models that are, not incidentally, also the models that have yielded major insights into IBD pathogenesis.
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Affiliation(s)
| | | | - Warren Strober
- Correspondence Address correspondence to: Warren Strober, MD, National Institutes of Health, Mucosal Immunity Section, 10 Center Drive, CRC Bldg. 10 5west-3940, Bethesda, Maryland 20892. fax: (301) 402-2240.
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Interleukin-18 gene promoter polymorphisms and celiac disease in Italian patients. Mol Biol Rep 2014; 42:525-33. [PMID: 25374428 DOI: 10.1007/s11033-014-3796-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Accepted: 10/14/2014] [Indexed: 01/05/2023]
Abstract
Celiac disease (CD) is the most common food-sensitive enteropathy in genetically susceptible individuals. The major genetic risk factors known are specific human leukocyte antigen (HLA)-DQ haplotypes, but other genetic factors are supposed to be involved. Interleukin-18 (IL-18) is a pro-inflammatory cytokine that has an important role in the immune defense and it has the potential to influence inflammatory disorders. IL-18 is able to promote Th1 cell development and it is expressed in the mucosa of the small intestine in celiac patients. Given the IL-18 biological role, and since a few studies have previously suggested its involvement in CD, in order to investigate the role of IL18 gene in the susceptibility to CD we have performed a case-control study, analyzing two IL18 gene promoter polymorphisms, previously reported to impair the transcriptional activity of the gene, (-137G > C and -607C > A, rs187238 and rs1946518 respectively). A total of 556 CD Italian patients and 582 controls, further stratified for HLA class II (DQ) CD risk haplotypes were enrolled. The -607A > C A allele and A/A genotype, as well as the combination of this allele with the -137G allele in the AG haplotype, were associated with an increased risk towards CD development, in particular in HLA-DQ2.2 patients. Although the association was very moderate, our results indicate the possible involvement of IL18 gene in the susceptibility to CD, and for this reason we do think it should deserve further investigation.
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Zhang J, Fu S, Sun S, Li Z, Guo B. Inflammasome activation has an important role in the development of spontaneous colitis. Mucosal Immunol 2014; 7:1139-50. [PMID: 24472848 PMCID: PMC4115056 DOI: 10.1038/mi.2014.1] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 12/23/2013] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease (IBD) is characterized for dysregulated intestinal inflammation. Conflicting reports have shown that activation of inflammasome could promote or decrease intestinal inflammation in an acute colitis model, whereas the involvement of inflammasome activation in chronic colitis is poorly understood. In this study, we investigated the role of inflammasome activation in the development of chronic intestinal inflammation by utilizing interleukin-10 (IL-10) knockout (KO) mouse as an animal model, which develops chronic colitis resembling human IBD. We demonstrate the causative link between inflammasome activation and the development of chronic intestinal inflammation. Our results show that mature IL-1β protein levels were significantly increased in all colon sections from IL-10-deficient mice compared with that of wild-type mice. We found that inhibition of inflammasome activities with IL-1 receptor antagonist or caspase-1 inhibitors suppressed IL-1β and IL-17 production from inflamed colon explants. Furthermore, blocking inflammasome activation with caspase-1 inhibitor in vivo significantly ameliorated the spontaneous colitis in IL-10 KO mice. Taken together, these observations demonstrate that inflammasome activation promotes the development of chronic intestinal inflammation.
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Affiliation(s)
- Jinyu Zhang
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040,Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040
| | - Shunjun Fu
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040,Department of Hepatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China
| | - Shaoli Sun
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425, United States of America
| | - Zihai Li
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040,Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040
| | - Beichu Guo
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040,Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040
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Saxena M, Yeretssian G. NOD-Like Receptors: Master Regulators of Inflammation and Cancer. Front Immunol 2014; 5:327. [PMID: 25071785 PMCID: PMC4095565 DOI: 10.3389/fimmu.2014.00327] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Accepted: 06/27/2014] [Indexed: 12/11/2022] Open
Abstract
Cytosolic NOD-like receptors (NLRs) have been associated with human diseases including infections, cancer, and autoimmune and inflammatory disorders. These innate immune pattern recognition molecules are essential for controlling inflammatory mechanisms through induction of cytokines, chemokines, and anti-microbial genes. Upon activation, some NLRs form multi-protein complexes called inflammasomes, while others orchestrate caspase-independent nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) signaling. Moreover, NLRs and their downstream signaling components engage in an intricate crosstalk with cell death and autophagy pathways, both critical processes for cancer development. Recently, increasing evidence has extended the concept that chronic inflammation caused by abberant NLR signaling is a powerful driver of carcinogenesis, where it abets genetic mutations, tumor growth, and progression. In this review, we explore the rapidly expanding area of research regarding the expression and functions of NLRs in different types of cancers. Furthermore, we particularly focus on how maintaining tissue homeostasis and regulating tissue repair may provide a logical platform for understanding the liaisons between the NLR-driven inflammatory responses and cancer. Finally, we outline novel therapeutic approaches that target NLR signaling and speculate how these could be developed as potential pharmaceutical alternatives for cancer treatment.
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Affiliation(s)
- Mansi Saxena
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai , New York, NY , USA
| | - Garabet Yeretssian
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai , New York, NY , USA ; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, NY , USA
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Gagliani N, Palm NW, de Zoete MR, Flavell RA. Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota. Int Immunol 2014; 26:495-9. [PMID: 24948595 DOI: 10.1093/intimm/dxu066] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammasomes are large cytosolic protein complexes that detect infection and stress-associated signals and promote immediate inflammatory responses. In the intestine, activation of the inflammasome leads to an inflammatory response that is important for controlling enteric infections but can also result in pathological tissue damage. Recent studies have suggested that the inflammasome also regulates intestinal homeostasis through its effects on the intestinal microbiota. Notably, many conflicting studies have been published regarding the effect of inflammasome deficiencies on intestinal homeostasis. Here, we attempt to reconcile these contrasting data by highlighting the many ways that the inflammasome contributes to intestinal homeostasis and pathology and exploring the potential role of alterations in the microbiota in these conflicting studies.
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Affiliation(s)
- Nicola Gagliani
- Department of Immunobiology, School of Medicine, Yale University, The Anlyan Center, 300 Cedar Street S560, S570 New Haven, CT 06519, USA
| | - Noah W Palm
- Department of Immunobiology, School of Medicine, Yale University, The Anlyan Center, 300 Cedar Street S560, S570 New Haven, CT 06519, USA
| | - Marcel R de Zoete
- Department of Immunobiology, School of Medicine, Yale University, The Anlyan Center, 300 Cedar Street S560, S570 New Haven, CT 06519, USA Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Richard A Flavell
- Department of Immunobiology, School of Medicine, Yale University, The Anlyan Center, 300 Cedar Street S560, S570 New Haven, CT 06519, USA Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
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35
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Corridoni D, Arseneau KO, Cominelli F. Functional defects in NOD2 signaling in experimental and human Crohn disease. Gut Microbes 2014; 5:340-4. [PMID: 24637801 PMCID: PMC4153771 DOI: 10.4161/gmic.28404] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Increasing evidence suggests that a deficit in innate immunity may play a causative role in the pathogenesis of inflammatory bowel disease. The most compelling support for this hypothesis comes from the genetic association of Crohn disease (CD) with carriage of polymorphisms within the NOD2 gene, which represent the most frequent genetic defect in CD. Our findings suggest that SAMP1/YitFc mice, which develop CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and impaired bacterial clearance before the onset of disease. This provides evidence that dysregulated NOD2 signaling, genetic or functional in nature, predisposes to chronic intestinal inflammation, and supports a new paradigm that CD may occur from a deficit in innate immunity as opposed to an overly aggressive immune response. This new paradigm could lead to potential development of new preventative or therapeutic modalities for patients with CD.
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Affiliation(s)
- Daniele Corridoni
- Department of Medicine; Case Western Reserve University; Cleveland, OH USA,Digestive Health Research Center; Case Western Reserve University; Cleveland, OH USA
| | - Kristen O Arseneau
- Department of Medicine; Case Western Reserve University; Cleveland, OH USA,Digestive Health Research Center; Case Western Reserve University; Cleveland, OH USA
| | - Fabio Cominelli
- Department of Medicine; Case Western Reserve University; Cleveland, OH USA,Digestive Health Research Center; Case Western Reserve University; Cleveland, OH USA,Correspondence to: Fabio Cominelli,
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36
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Spyropoulos BG. Interleukin-18 as a target for modulation of irinotecan-induced intestinal toxicity: a step towards a better therapeutic index?: Commentary on Lima-Junior et al., Br J Pharmacol 171: 2335-2350. Br J Pharmacol 2014; 172:4779-81. [PMID: 24724613 DOI: 10.1111/bph.12719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 04/03/2014] [Indexed: 12/26/2022] Open
Affiliation(s)
- B G Spyropoulos
- First Department of Propaedeutic Surgery, School of Medicine, University of Athens, Athens, Greece
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37
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Lopetuso LR, Chowdhry S, Pizarro TT. Opposing Functions of Classic and Novel IL-1 Family Members in Gut Health and Disease. Front Immunol 2013; 4:181. [PMID: 23847622 PMCID: PMC3705591 DOI: 10.3389/fimmu.2013.00181] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 06/24/2013] [Indexed: 12/17/2022] Open
Abstract
In addition to their well-established role(s) in the pathogenesis of gastrointestinal (GI)-related inflammatory disorders, including inflammatory bowel disease (IBD) and inflammation-associated colorectal cancer (CRC), emerging evidence confirms the critical involvement of the interleukin-1 (IL-1) cytokine family and their ligands in the maintenance of normal gut homeostasis. In fact, the paradigm that IBD occurs in two distinct phases is substantiated by the observation that classic IL-1 family members, such as IL-1, the IL-1 receptor antagonist (IL-1Ra), and IL-18, possess dichotomous functions depending on the phase of disease, as well as on their role in initiating vs. sustaining chronic gut inflammation. Another recently characterized IL-1 family member, IL-33, also possesses dual functions in the gut. IL-33 is upregulated in IBD and potently induces Th2 immune responses, while also amplifying Th1-mediated inflammation. Neutralization studies in acute colitis models, however, have yielded controversial results and recent reports suggest a protective role of IL-33 in epithelial regeneration and mucosal wound healing. Finally, although little is currently known regarding the potential contribution of IL-36 family members in GI inflammation/homeostasis, another IL-1 family member, IL-37, is emerging as a potent anti-inflammatory cytokine with the ability to down-regulate colitis. This new body of information has important translational implications for both the prevention and treatment of patients suffering from IBD and inflammation-associated CRC.
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Affiliation(s)
- Loris R Lopetuso
- Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH , USA ; Internal Medicine, Gastroenterology Division, Catholic University of Rome , Rome , Italy
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38
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The role of IL-33 in gut mucosal inflammation. Mediators Inflamm 2013; 2013:608187. [PMID: 23766561 PMCID: PMC3676953 DOI: 10.1155/2013/608187] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 05/09/2013] [Indexed: 02/04/2023] Open
Abstract
Interleukin (IL)-33 is a recently identified cytokine belonging to the IL-1 family that is widely expressed throughout the body and has the ability to induce Th2 immune responses. In addition, IL-33 plays a key role in promoting host defenses against parasites through the expansion of a novel population of innate lymphoid cells. In recent years, a growing body of evidence has shown that the proinflammatory properties displayed by IL-33 are detrimental in several experimental models of inflammation; in others, however, IL-33 appears to have protective functions. In 2010, four different research groups consistently described the upregulation of IL-33 in patients with inflammatory bowel disease (IBD). Animal models of IBD were subsequently utilized in order to mechanistically determine the precise role of IL-33 in chronic intestinal inflammation, without, however, reaching conclusive evidence demonstrating whether IL-33 is pathogenic or protective. Indeed, data generated from these studies suggest that IL-33 may possess dichotomous functions, enhancing inflammatory responses on one hand and promoting epithelial integrity on the other. This review focuses on the available data regarding IL-33/ST2 in the physiological and inflammatory states of the gut in order to speculate on the possible roles of this novel IL-1 family member in intestinal inflammation.
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39
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Okanishi H, Hayashi K, Sakamoto Y, Sano T, Maruyama H, Kagawa Y, Watari T. NOD2 mRNA Expression and NFkappaB Activation in Dogs with Lymphocytic Plasmacytic Colitis. J Vet Intern Med 2013; 27:439-44. [PMID: 23600687 DOI: 10.1111/jvim.12082] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 02/02/2013] [Accepted: 03/05/2013] [Indexed: 12/15/2022] Open
Affiliation(s)
- H. Okanishi
- Laboratory of Comprehensive Veterinary Clinical Studies
| | - K. Hayashi
- Laboratory of Comprehensive Veterinary Clinical Studies
| | - Y. Sakamoto
- Laboratory of Comprehensive Veterinary Clinical Studies
| | - T. Sano
- Laboratory of Comprehensive Veterinary Clinical Studies
| | - H. Maruyama
- Laboratory of Veterinary Pathobiology (Maruyama); Department of Veterinary Medicine; College of Bioresource Sciences; Nihon University; Kanagawa Japan
| | | | - T. Watari
- Laboratory of Comprehensive Veterinary Clinical Studies
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40
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Nishio J, Honda K. Immunoregulation by the gut microbiota. Cell Mol Life Sci 2012; 69:3635-50. [PMID: 22527722 PMCID: PMC11114866 DOI: 10.1007/s00018-012-0993-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 03/29/2012] [Accepted: 04/03/2012] [Indexed: 12/21/2022]
Abstract
The human intestinal mucosa is constantly exposed to commensal microbiota. Since the gut microbiota is beneficial to the host, hosts have evolved intestine-specific immune systems to co-exist with the microbiota. On the other hand, the intestinal microbiota actively regulates the host's immune system, and recent studies have revealed that specific commensal bacterial species induce the accumulation of specific immune cell populations. For instance, segmented filamentous bacteria and Clostridium species belonging to clusters XIVa and IV induce the accumulation of Th17 cells in the small intestine and Foxp3(+) regulatory T cells in the large intestine, respectively. The immune cells induced by the gut microbiota likely contribute to intestinal homeostasis and influence systemic immunity in the host.
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Affiliation(s)
- Junko Nishio
- Department of Immunology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033 Japan
| | - Kenya Honda
- Department of Immunology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033 Japan
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41
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Lopetuso LR, Scaldaferri F, Pizarro TT. Emerging role of the interleukin (IL)-33/ST2 axis in gut mucosal wound healing and fibrosis. FIBROGENESIS & TISSUE REPAIR 2012; 5:18. [PMID: 23062310 PMCID: PMC3514189 DOI: 10.1186/1755-1536-5-18] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 08/31/2012] [Indexed: 01/27/2023]
Abstract
Interleukin (IL)-33 (IL-1F11) is the newest member of the IL-1Family of cytokines and has been best characterized as a potent inducer of T helper (Th)2 immune responses. Increasing evidence, however, indicates that IL-33 also represents an important mediator of mucosal healing and epithelial restoration and repair. As such, IL-33 follows the trend of several innate-type cytokines, including members of the IL-1Family (for example, IL-1α, IL-1β, and IL-18), that possess dichotomous roles of inducing a potent proinflammatory response, while also promoting protection and the return to immune homeostasis. This dual function is best depicted in the gut mucosa and is dependent upon the immunological/genetic status of the host and/or the type and phase of the ongoing inflammatory process. IL-33 has also been described as a prototypic 'alarmin' that has the ability to signal local, innate immune responses of trauma or infection in an effort to mount an effective, physiologic inflammatory reaction to induce mucosal healing and restore normal gut equilibrium. Finally, several recent studies have reported the role of IL-33 during fibrogenesis as fibrosis is commonly thought to occur as the end stage of dysregulated wound healing wherein chronic tissue damage is paired with uncontrolled activation of mesenchymal cells. Taken together, aside from its established function of promoting potent Th2 immune responses, IL-33 is emerging as an important cytokine for the induction of mucosal healing and restoration of intestinal homeostasis, as well as playing a central role in fibrosis and wound repair. The present review will focus on what is currently known regarding IL-33's role in gut mucosal wound healing and fibrosis, as well as touch on its potential contribution to tumorigenesis and GI-related cancer, an alternate outcome of dysregulated epithelial proliferation.
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Affiliation(s)
- Loris R Lopetuso
- Department of Pathology, Case Western Reserve University School of Medicine, 2103 Cornell Road, WRB 5534, Cleveland, OH, 44106, USA.
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42
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Bamias G, Corridoni D, Pizarro TT, Cominelli F. New insights into the dichotomous role of innate cytokines in gut homeostasis and inflammation. Cytokine 2012; 59:451-459. [PMID: 22795953 PMCID: PMC3652608 DOI: 10.1016/j.cyto.2012.06.014] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Accepted: 06/04/2012] [Indexed: 02/08/2023]
Abstract
In addition to their well-known role in acute injury and chronic inflammation, "innate" cytokines play an important role in health and the maintenance of normal immune homeostasis. This group includes the prototypic cytokines IL-1 and TNFα, as well as several other members belonging to the IL-1 and TNF family, such as IL-18, IL-33, IL-36-38, and TL1A. The dichotomous role of these cytokines has been best characterized in the intestine where innate cytokines may play both a protective and a pro-inflammatory role, depending upon the immmunological status of the host or the type and phase of the inflammatory process. This new information has produced novel pathogenetic hypotheses that have important translational implications both in regard to the prevention and treatment of chronic intestinal inflammation, including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease. This review will discuss and summarize current data regarding the role of IL-1, TNFα, and their family members in regulating gut mucosal homeostasis and chronic intestinal inflammation.
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Affiliation(s)
- Giorgos Bamias
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44122, USA
- GI Division-1 Department of Propaedeutic and Internal Medicine, “Laikon” General Hospital, Athens University Medical School, Athens 11527, Greece
| | - Daniele Corridoni
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44122, USA
- Department of Digestive Health Research Center, Case Western Reserve University, Cleveland, OH 44122, USA
| | - Theresa T. Pizarro
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44122, USA
- Department of Digestive Health Research Center, Case Western Reserve University, Cleveland, OH 44122, USA
| | - Fabio Cominelli
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44122, USA
- Department of Digestive Health Research Center, Case Western Reserve University, Cleveland, OH 44122, USA
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43
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Kim JM. [Inflammatory bowel diseases and inflammasome]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 58:300-10. [PMID: 22198227 DOI: 10.4166/kjg.2011.58.6.300] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1b, IL-18 and tumor necrosis factor-a, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (> 700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1b and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD.
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Affiliation(s)
- Jung Mogg Kim
- Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea.
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44
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Lapointe TK, Buret AG. Interleukin-18 facilitates neutrophil transmigration via myosin light chain kinase-dependent disruption of occludin, without altering epithelial permeability. Am J Physiol Gastrointest Liver Physiol 2012; 302:G343-51. [PMID: 22135309 DOI: 10.1152/ajpgi.00202.2011] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Compromised epithelial barrier function and tight junction alterations are hallmarks of a number of gastrointestinal disorders, including inflammatory bowel disease (IBD). Increased levels of IL-18 have been observed in mucosal samples from Crohn's disease and ulcerative colitis patients. Remarkably, several reports have demonstrated that immunological or genetic blockage of IL-18 ameliorates the severity of colitis in multiple in vivo models of IBD. Nevertheless, the effects of IL-18 on intestinal epithelial barrier function remain unclear. We hypothesized that IL-18 could disrupt intestinal epithelial barrier structure and function, thus contributing to tissue damage in the context of IBD. The aims of the present study were to determine the effects of IL-18 on epithelial barrier structure and function and to characterize the mechanisms involved in these modulatory properties. Human colonic epithelial Caco-2 monolayers were coincubated with IL-18 for 24 h and processed for immunocytochemistry, immunoblotting, quantitative PCR, and permeability measurements (transepithelial resistance, FITC-dextran fluxes, and bacterial translocation). Our findings indicate that IL-18 selectively disrupts tight junctional occludin, without affecting the distribution pattern of claudin-4, claudin-5, zonula occludens-1, or E-cadherin. This effect coincided with a significant increase in myosin light chain kinase (MLCK) protein levels and activity. Pharmacological inhibition of MLCK and NF-κB prevented IL-18-induced loss of occludin. Although too subtle to alter paracellular permeability, these fine changes correlated with an MLCK-dependent increase in neutrophil transepithelial migration. In conclusion, our data suggest that IL-18 may potentiate inflammation in the context of IBD by facilitating neutrophil transepithelial migration via MLCK-dependent disruption of tight junctional occludin.
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Affiliation(s)
- Tamia K Lapointe
- Dept. of Biological Sciences, Univ. of Calgary, Calgary, AB, Canada
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45
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Abstract
Colorectal cancer is a major health problem in developed countries. Chronic intestinal inflammation predisposes individuals to the development of colorectal cancer. The intracellular NOD-like receptors (NLRs) have emerged as crucial regulators of intestinal inflammation and colorectal tumorigenesis. Activation of several NLRs leads to the formation of a protein complex called the inflammasome, which then triggers the activation of the cysteine protease caspase-1 and the downstream maturation and secretion of the inflammatory cytokines interleukin-1β and -18. Defective inflammasome signaling in the gut contributes to colitis and colorectal tumorigenesis by increasing the permeability of the epithelial barrier, dysregulating the proliferation of epithelial cells, and inducing oncogenic mediators. In this review, we discuss our current knowledge on how the inflammasome protects against colorectal tumorigenesis.
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Affiliation(s)
- Md Hasan Zaki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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46
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NOD-like receptors and the innate immune system: Coping with danger, damage and death. Cytokine Growth Factor Rev 2011; 22:257-76. [DOI: 10.1016/j.cytogfr.2011.09.003] [Citation(s) in RCA: 146] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Accepted: 09/07/2011] [Indexed: 12/26/2022]
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Pastorelli L, De Salvo C, Cominelli MA, Vecchi M, Pizarro TT. Novel cytokine signaling pathways in inflammatory bowel disease: insight into the dichotomous functions of IL-33 during chronic intestinal inflammation. Therap Adv Gastroenterol 2011; 4:311-23. [PMID: 21922030 PMCID: PMC3165208 DOI: 10.1177/1756283x11410770] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
In 2010, four independent groups almost simultaneously reported the association of the novel interleukin-1 (IL-1) family member, IL-33, with inflammatory bowel disease (IBD). The findings were remarkably consistent and demonstrated that IL-33 is markedly upregulated in, and specific to, ulcerative colitis (UC). In addition, although a variety of gut-associated immune cell subsets express IL-33, the primary source appears to be the intestinal epithelium. IL-33's receptor, ST2, a formerly orphaned IL-1 receptor-related protein, was also found to be increased in UC patients, although the cellular source of ST2 appears to be somewhat more ambiguous. In fact, emerging evidence indicates that the IL-33/ST2 axis plays a critical role in several other chronic inflammatory and immune disorders. In the gut, IL-33 has been shown to be important in the clearance of intestinal parasites, and inducing epithelial cell hyperplasia, mucus production and mucosal eosinophilic infiltration. However, despite the established trend of increased IL-33 and ST2 expression during IBD, specifically UC, the precise pathophysiologic relevance of these findings has yet to be determined. Interestingly, IL-33 has the ability to potentiate pathogenic Th2 and Th17 responses in gut-associated lymphoid tissues, while also promoting healing of damaged mucosa following inflammatory insults. Indeed, further mechanistic studies are warranted to confirm the possible dichotomous functions of IL-33 during chronic intestinal inflammation and better define its precise role in the pathogenesis of IBD. Herein, we discuss what is currently known about IL-33/ST2 in the gut and speculate as to the potential role of the IL-33/ST2 system in IBD.
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Affiliation(s)
- Luca Pastorelli
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; IRCCS Policlinico San Donato, Gastroenterology and Gastrointestinal Endoscopy Unit, San Donato Milanese, Italy; University of Milan School of Medicine, Medical and Surgical Sciences, Milan, Italy
| | - Carlo De Salvo
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Marissa A. Cominelli
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Maurizio Vecchi
- IRCCS Policlinico San Donato, Gastroenterology and Gastrointestinal Endoscopy Unit, San Donato Milanese, Italy; University of Milan School of Medicine, Medical and Surgical Sciences, Milan, Italy
| | - Theresa T. Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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48
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Zaki MH, Lamkanfi M, Kanneganti TD. The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends Immunol 2011; 32:171-9. [PMID: 21388882 DOI: 10.1016/j.it.2011.02.002] [Citation(s) in RCA: 229] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 01/31/2011] [Accepted: 02/01/2011] [Indexed: 01/11/2023]
Abstract
Inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis constitute a major health problem in developed countries. Moreover, IBD predisposes to the development of colorectal cancer. The intracellular NOD-like receptor Nlrp3 is rapidly emerging as a crucial regulator of intestinal homeostasis. This innate immune receptor mediates assembly of the inflammasome complex in the presence of microbial ligands, triggering caspase-1 activation and secretion of IL-1β and IL-18. Recent studies suggest that defective Nlrp3 inflammasome signaling in the gut contributes to IBD through increased permeability across the epithelial barrier and the induction of detrimental immune responses against invading commensals. Here, we review and discuss recent advances of the role of the Nlrp3 inflammasome in colitis and colon tumorigenesis.
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Affiliation(s)
- Md Hasan Zaki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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49
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Saleh M, Trinchieri G. Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol 2010; 11:9-20. [PMID: 21151034 DOI: 10.1038/nri2891] [Citation(s) in RCA: 314] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The innate immune system provides first-line defences in response to invading microorganisms and endogenous danger signals by triggering robust inflammatory and antimicrobial responses. However, innate immune sensing of commensal microorganisms in the intestinal tract does not lead to chronic intestinal inflammation in healthy individuals, reflecting the intricacy of the regulatory mechanisms that tame the inflammatory response in the gut. Recent findings suggest that innate immune responses to commensal microorganisms, although once considered to be harmful, are necessary for intestinal homeostasis and immune tolerance. This Review discusses recent findings that identify a crucial role for innate immune effector molecules in protection against colitis and colitis-associated colorectal cancer and the therapeutic implications that ensue.
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Affiliation(s)
- Maya Saleh
- Department of Medicine, McGill University, Montreal, Quebec, H3G 0B1 Canada.
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50
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Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. THE JOURNAL OF IMMUNOLOGY 2010; 185:4912-20. [PMID: 20855874 DOI: 10.4049/jimmunol.1002046] [Citation(s) in RCA: 328] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer is a leading cause of cancer-related deaths worldwide. Chronic inflammation is recognized as a predisposing factor for the development of colon cancer, but the molecular mechanisms linking inflammation and tumorigenesis have remained elusive. Recent studies revealed a crucial role for the NOD-like receptor protein Nlrp3 in regulating inflammation through the assembly of proinflammatory protein complexes termed inflammasomes. However, its role in colorectal tumor formation remains unclear. In this study, we showed that mice deficient for Nlrp3 or the inflammasome effector caspase-1 were highly susceptible to azoxymethane/dextran sodium sulfate-induced inflammation and suffered from dramatically increased tumor burdens in the colon. This was a consequence of markedly reduced IL-18 levels in mice lacking components of the Nlrp3 inflammasome, which led to impaired production and activation of the tumor suppressors IFN-γ and STAT1, respectively. Thus, IL-18 production downstream of the Nlrp3 inflammasome is critically involved in protection against colorectal tumorigenesis.
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Affiliation(s)
- Mohammad Hasan Zaki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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