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Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

ABSTRACT: Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8⁺ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8⁺ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8⁺ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.

SUBMITTER: Wang Z

PROVIDER: S-EPMC8770466 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

Wang Zhen Z Zeng Fan-Lian FL Hu Ya-Wen YW Wang Xiao-Yan XY Zhao Fu-Lei FL Zhou Pei P Hu Jing J Xiao Yuan-Yuan YY Hu Zhong-Lan ZL Guo Ming-Feng MF Wei Xiao-Qiong XQ Liu Xiao X Huang Nong-Yu NY Zhang Jun J Chen Shu-Wen SW Cheng Juan J Zheng Hua-Ping HP Zhou Hong H Zhao Qi-Xiang QX Zhang Chen C Hao Yan Y Zou Song S Gui Yi-Yue YY Yu Jia-Dong JD Gu Lin-Na LN Yue Cheng-Cheng CC Zhang Hao-Zhou HZ Wu Wen-Ling WL Zhou Yi-Fan YF Zhou Xi-Kun XK Shen Guo-Bo GB Teng Xiu X Li Jiong J Li Jiong J

Signal transduction and targeted therapy 20220120 1

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and m ...[more]

PMID: 35046386

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Project description:Background: Inflammatory bowel disease (IBD) involves complicated crosstalk between host immunity and the gut microbiome, whereas the mechanics of how they govern intestinal inflammation remain poorly understood. In this study, we investigated the contribution of environmental factors to shaping gut microbiota composition in colitis mice that were transgenic for human IL-37, a natural anti-inflammatory cytokine possessing pathogenic and protective functions related to microbiota alterations. Methods: Mice transgenic expressing human IL-37 (IL-37tg) were housed under conventional and specific pathogen-free (SPF) conditions to develop a mouse model of dextran sulfate sodium (DSS)-induced colitis. 16S ribosomal RNA sequencing was used for analyzing fecal microbial communities. The efficacy of microbiota in the development of colitis in IL-37tg mice was investigated after antibiotic treatment and fecal microbiota transplantation (FMT). The mechanism by which IL-37 worsened colitis was studied by evaluating intestinal epithelial barrier function, immune cell infiltration, the expression of diverse cytokines and chemokines, as well as activated signaling pathways. Results: We found that IL-37 overexpression aggravated DSS-induced colitis in conventional mice but protected against colitis in SPF mice. These conflicting results from IL-37tg colitis mice are ascribed to a dysbiosis of the gut microbiota in which detrimental bacteria increased in IL-37tg conventional mice. We further identified that the outcome of IL-37-caused colon inflammation is strongly related to intestinal epithelial barrier impairment caused by pathogenic bacteria, neutrophils, and NK cells recruitment in colon lamina propria and mesenteric lymph node to enhance inflammatory responses in IL-37tg conventional mice. Conclusions: The immunoregulatory properties of IL-37 are detrimental in the face of dysbiosis of the intestinal microbiota, which contributes to exacerbated IBD occurrences that are uncontrollable by the immune system, suggesting that depleting gut pathogenic bacteria or maintaining intestinal microbial and immune homeostasis could be a promising therapeutic strategy for IBD.

Dataset Information

Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

Publications

Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

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