IL-37d Negatively Regulates NLRP3 Transcription via Receptor-mediated Pathway and Alleviates DSS-induced Colitis

Li, Yuan; Chu, Hongxia; Zhao, Meihua; Li, Chaoze; Guan, Yetong; Guo, Chun; Li, Yan; Wang, Qun; Shi, Yongyu; Zhu, Faliang; Zhang, Lining

doi:10.1093/ibd/izaa124

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…However, it should be highlighted that the colitis induced by IL-37 was only observed in experimental animals maintained in conventional facilities, whereas the protective effects were observed in colitis under SPF experimental settings. This is in line with previous observations that IL-37 derived either from hematopoietic cells, or mesenchymal stromal cells, or T cells, is sufficient to curb colon inflammation in SPF mice 20 , 21 , 33 , 34 . Indeed, the protective and pathogenic functions of IL-37 during colitis were consistent with those of other members of the IL-1 family, including IL-1, IL-33, and IL-36 35 - 38 .…”

Section: Discussionsupporting

confidence: 92%

Interleukin-37 exacerbates experimental colitis in an intestinal microbiome-dependent fashion

Cong¹,

Wen²,

Dai³

et al. 2022

Theranostics

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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.

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Section: Discussionsupporting

confidence: 92%

Interleukin-37 exacerbates experimental colitis in an intestinal microbiome-dependent fashion

Cong¹,

Wen²,

Dai³

et al. 2022

Theranostics

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“…IL-37d transgenic mice show increased resistance to DSSinduced acute colitis and inhibition of NLRP3 inflammasome overactivation. 228 In addition, peritoneal tissue-resident macrophages lacking the tissue-specific transcription factor GATA6 robustly suppressed IL-1β processing through the action of Gata6mediated production of prostacyclin and IL-10. 229 Further studies will be needed to evaluate the regulatory effect of a wide range of cytokines on NLRP3 inflammasome activation.…”

Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

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“…In addition, IL-37 inhibits the oligomerization/speck formation (which is a step in inflammasome activation and subsequent caspase-1 activation) and pyrolysis (-50%) of apoptosis-associated speck-like protein containing a CARD induced by nigericin and silica (38). Moreover, IL-37d downregulates the expression of NLRP3 at the priming step through the suppression of NF-kB activation by transcriptional profiling, and inhibits NLRP3 inflammasome activation (39). The use of Si-IL-1R8 and MCC-950, a potent and selective inhibitor of the NLRP3 inflammasome, further demonstrates the vital role of IL-1R8 and NLRP3 in the anti-inflammatory effects of IL-37 (40).…”

Section: In Vitro and In Vivo Anti-inflammatory Effects Of Il-37mentioning

confidence: 99%

Current Understanding of IL-37 in Human Health and Disease

Tao

2021

Front. Immunol.

116

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IL-37 is a recently discovered cytokine in the IL-1 family exerting broad protective effects on inflammatory diseases, autoimmune diseases, and cancer. Immune and non-immune cells produce the IL-37 precursor upon pro-inflammatory stimuli. Intracellularly, caspase-1 cleaves and activates IL-37, and its mature form binds to Smad3; this complex translocates into the nucleus where it suppresses cytokine production, consequently reducing inflammation. Extracellularly, IL-37 forms a complex with IL-18Rα and IL-1R8 (formerly TIR8 or SIGIRR) that transduces anti-inflammatory signals by the suppression of NF-κB and MAPK and the activation of Mer-PTEN-DOK pathways. During inflammation, IL-37 suppresses the expression of several pro-inflammatory cytokine in favor to the expression of the anti-inflammatory ones by the regulation of macrophage polarization, lipid metabolism, inflammasome function, TSLP synthesis and miRNAs function. Moreover, IL-37 not only regulates the innate and acquired immunity, but also improves aging-associated immunosenescence. Furthermore, IL-37 exerts an inhibitory effect on tumor angiogenesis and metastasis, and progression. Finally, IL-37 may have a potential ability to reduce excessive inflammation since it is aberrantly expressed in patients with inflammatory diseases, autoimmune diseases, and cancer, thus, it may be used as a marker for different types of diseases. Therefore, this review provides an updated view of the role of IL-37 in human health and disease, and discusses the potential of IL-37 as a therapeutic target and biomarker in inflammatory diseases, autoimmune diseases, and cancer.

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IL-37d Negatively Regulates NLRP3 Transcription via Receptor-mediated Pathway and Alleviates DSS-induced Colitis

Cited by 17 publications

References 29 publications

Interleukin-37 exacerbates experimental colitis in an intestinal microbiome-dependent fashion

Interleukin-37 exacerbates experimental colitis in an intestinal microbiome-dependent fashion

An update on the regulatory mechanisms of NLRP3 inflammasome activation

Current Understanding of IL-37 in Human Health and Disease

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