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Tran LS, Ying L, D'Costa K, Wray-McCann G, Kerr G, Le L, Allison CC, Ferrand J, Chaudhry H, Emery J, De Paoli A, Colon N, Creed S, Kaparakis-Liaskos M, Como J, Dowling JK, Johanesen PA, Kufer TA, Pedersen JS, Mansell A, Philpott DJ, Elgass KD, Abud HE, Nachbur U, Croker BA, Masters SL, Ferrero RL. NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice. Nat Commun 2023; 14:3804. [PMID: 37365163 DOI: 10.1038/s41467-023-39487-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 06/15/2023] [Indexed: 06/28/2023] Open
Abstract
The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.
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Affiliation(s)
- L S Tran
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - L Ying
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - K D'Costa
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - G Wray-McCann
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - G Kerr
- Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - L Le
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - C C Allison
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J Ferrand
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - H Chaudhry
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J Emery
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - A De Paoli
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - N Colon
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - S Creed
- Monash Micro Imaging, Monash University, Melbourne, VIC, Australia
| | - M Kaparakis-Liaskos
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J Como
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J K Dowling
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - P A Johanesen
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - T A Kufer
- Department of Immunology, University of Hohenheim, Institute of Nutritional Medicine, Stuttgart, Germany
| | | | - A Mansell
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - D J Philpott
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - K D Elgass
- Monash Micro Imaging, Monash University, Melbourne, VIC, Australia
| | - H E Abud
- Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - U Nachbur
- Cell Signalling and Cell Death Division, WEHI, Melbourne, VIC, Australia
| | - B A Croker
- Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Inflammation Division, WEHI, Melbourne, VIC, Australia
| | - S L Masters
- Inflammation Division, WEHI, Melbourne, VIC, Australia
| | - R L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
- Inflammation Division, WEHI, Melbourne, VIC, Australia.
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Alexander SM, Retnakumar RJ, Chouhan D, Devi TNB, Dharmaseelan S, Devadas K, Thapa N, Tamang JP, Lamtha SC, Chattopadhyay S. Helicobacter pylori in Human Stomach: The Inconsistencies in Clinical Outcomes and the Probable Causes. Front Microbiol 2021; 12:713955. [PMID: 34484153 PMCID: PMC8416104 DOI: 10.3389/fmicb.2021.713955] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022] Open
Abstract
Pathogenic potentials of the gastric pathogen, Helicobacter pylori, have been proposed, evaluated, and confirmed by many laboratories for nearly 4 decades since its serendipitous discovery in 1983 by Barry James Marshall and John Robin Warren. Helicobacter pylori is the first bacterium to be categorized as a definite carcinogen by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO). Half of the world’s population carries H. pylori, which may be responsible for severe gastric diseases like peptic ulcer and gastric cancer. These two gastric diseases take more than a million lives every year. However, the role of H. pylori as sole pathogen in gastric diseases is heavily debated and remained controversial. It is still not convincingly understood, why most (80–90%) H. pylori infected individuals remain asymptomatic, while some (10–20%) develop such severe gastric diseases. Moreover, several reports indicated that colonization of H. pylori has positive and negative associations with several other gastrointestinal (GI) and non-GI diseases. In this review, we have discussed the state of the art knowledge on “H. pylori factors” and several “other factors,” which have been claimed to have links with severe gastric and duodenal diseases. We conclude that H. pylori infection alone does not satisfy the “necessary and sufficient” condition for developing aggressive clinical outcomes. Rather, the cumulative effect of a number of factors like the virulence proteins of H. pylori, local geography and climate, genetic background and immunity of the host, gastric and intestinal microbiota, and dietary habit and history of medicine usage together determine whether the H. pylori infected person will remain asymptomatic or will develop one of the severe gastric diseases.
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Affiliation(s)
| | | | - Deepak Chouhan
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India.,Centre for Doctoral Studies, Manipal Academy of Higher Education, Manipal, India
| | | | | | - Krishnadas Devadas
- Department of Gastroenterology, Government Medical College, Trivandrum, India
| | - Namrata Thapa
- Biotech Hub, Department of Zoology, Nar Bahadur Bhandari Degree College, Gangtok, India
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Negovan A, Iancu M, Fülöp E, Bănescu C. Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions. World J Gastroenterol 2019; 25:4105-4124. [PMID: 31435167 PMCID: PMC6700706 DOI: 10.3748/wjg.v25.i30.4105] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/12/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis, due largely to late diagnosis. The importance of the interaction between Helicobacter pylori (H. pylori) infection, the main risk factor, and host-related genetic factors has been studied intensively in recent years. The genetic predisposition for non-hereditary gastric cancer is difficult to assess, as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined. For non-cardiac intestinal-type cancer, identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies. The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H. pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia; the literature now includes various and non-conclusive results on this topic. The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions. Among the investigated gene variants onlyIL10T-819C, IL-8-251, IL-18RAP917997, IL-22 rs1179251, IL1-B-511, IL1-B-3954, IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk. One of the most important limiting factors is the inhomogeneity of the studies (e.g., the lack of data on concomitant H. pylori infection, methods used to assess preneoplastic lesions, and source population). Testing the modifying effect of H. pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions, or even testing the interaction between H. pylori and cytokine gene variants in multivariable models adjusted for potential covariates, could increase generalizability of results.
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Affiliation(s)
- Anca Negovan
- Department of Clinical Science-Internal Medicine, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Mureș 540139, Romania
| | - Mihaela Iancu
- Department of Medical Informatics and Biostatistics, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Cluj 400349, Romania
| | - Emőke Fülöp
- Department of Morphological Sciences, Histology, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Mureș 540139, Romania
| | - Claudia Bănescu
- Genetics Laboratory, Center for Advanced Medical and Pharmaceutical Research, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Mureș 540139, Romania
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Tran LS, Chonwerawong M, Ferrero RL. Regulation and functions of inflammasome-mediated cytokines in Helicobacter pylori infection. Microbes Infect 2017; 19:449-458. [PMID: 28690082 DOI: 10.1016/j.micinf.2017.06.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 06/22/2017] [Indexed: 02/08/2023]
Abstract
Persistent stomach infection with Helicobacter pylori causes chronic mucosal inflammation (gastritis), which is widely recognized as an essential precursor to gastric cancer. The IL-1 interleukin family cytokines IL-1β and IL-18 have emerged as central mediators of mucosal inflammation. Here, we review the regulation and functions of these cytokines in H. pylori-induced inflammation and carcinogenesis.
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Affiliation(s)
- Le Son Tran
- Centre for Innate Immunity and Infectious Diseases, The Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia
| | - Michelle Chonwerawong
- Centre for Innate Immunity and Infectious Diseases, The Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, The Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Wellington Road, Clayton, Victoria, Australia.
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