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      Inflammasomes and Cancer: The Dynamic Role of the Inflammasome in Tumor Development

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          Abstract

          Chronic Inflammation in tumor microenvironments is not only associated with various stages of tumor development, but also has significant impacts on tumor immunity and immunotherapy. Inflammasome are an important innate immune pathway critical for the production of active IL-1β and interleukin 18, as well as the induction of pyroptosis. Although extensive studies have demonstrated that inflammasomes play a vital role in infectious and autoimmune diseases, their role in tumor progression remains elusive. Multiple studies using a colitis-associated colon cancer model show that inflammasome components provide protection against the development of colon cancer. However, very recent studies demonstrate that inflammasomes promote tumor progression in skin and breast cancer. These results indicate that inflammasomes can promote and suppress tumor development depending on types of tumors, specific inflammasomes involved, and downstream effector molecules. The complicated role of inflammasomes raises new opportunities and challenges to manipulate inflammasome pathways in the treatment of cancer.

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          Most cited references99

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          Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a Gasdermin

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            Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

            Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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              Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.

              Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 September 2017
                2017
                : 8
                : 1132
                Affiliations
                [1] 1Department of Microbiology and Immunology, Medical University of South Carolina (MUSC) , Charleston, SC, United States
                [2] 2Hollings Cancer Center, Medical University of South Carolina (MUSC) , Charleston, SC, United States
                Author notes

                Edited by: Masoud H. Manjili, Virginia Commonwealth University, United States

                Reviewed by: Tsan Sam Xiao, Case Western Reserve University, United States; Kyle K. Payne, Wistar Institute, United States

                *Correspondence: Beichu Guo, guobe@ 123456musc.edu

                Specialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.01132
                5600922
                28955343
                8520c874-6a05-4626-9d72-1f85252dac46
                Copyright © 2017 Kantono and Guo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 June 2017
                : 28 August 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 146, Pages: 9, Words: 8179
                Funding
                Funded by: American Cancer Society 10.13039/100000048
                Award ID: 15040530
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: 1P01CA203628
                Categories
                Immunology
                Review

                Immunology
                inflammasome,tumor microenvironments,nod-like receptors,il-1,tumor,inflammation,immunotherapy
                Immunology
                inflammasome, tumor microenvironments, nod-like receptors, il-1, tumor, inflammation, immunotherapy

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