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

Background Interleukin-37 (IL-37) is a new negative immune regulator. It has 5 splicing forms, IL-37a-e, and most research mainly focuses on IL-37b functions in diverse diseases. Our previous research found that IL-37d inhibits lipopolysaccharide-induced inflammation in endotoxemia through a mechanism different from that of IL-37b. However, whether IL-37d plays a role in colitis and the underlying mechanisms is still obscure. Herein, we identified whether IL-37d regulates NLRP3 inflammasome activity and determined its effect on colitis. Methods NLRP3 inflammasome in macrophages from IL-37d transgenic (IL-37dtg) and control wild type (WT) mice were activated by lipopolysaccharide and adenosine 5 '-triphosphate. The expression of NLRP3 inflammasome components and its downstream effector, IL-1 beta, were detected by real-time polymerase chain reaction, western blot, and ELISA. The models of alum-induced peritonitis and dextran sodium sulfate (DSS)-induced colitis were used to investigate the function of IL-37d on regulating the activity of NLRP3 inflammasome in vivo. Results Our results showed that the activation of NLRP3 inflammasome in macrophage and alum-induced peritonitis was inhibited by IL-37d. Strikingly, IL-37d suppressed NLRP3 expression at the priming step via inhibiting NF-kappa B activation by transcriptional profiling. Moreover, the recombinant protein IL-37d attenuated NLRP3 inflammasome activation and the production of IL-1 beta, which could be reversed by IL-1R8 knockdown. Finally, IL-37d transgenic mice resisted DSS-induced acute colitis and NLRP3 inflammasome activation. Conclusion Interleukin-37d inhibits overactivation of the NLRP3 inflammasome through regulating NLRP3 transcription in an IL-1R8 receptor-mediated signaling pathway. In summary, IL-37d suppresses inflammasome activation through inhibiting NLRP3 transcription in a receptor-dependent manner. Further, IL-37d could alleviate DSS-induced colitis by inhibiting NLRP3 inflammasome activation.

Automated summary

IL-37d inhibits the overactivation of NLRP3 inflammasome through regulating NLRP3 transcription in macrophages, mediated by IL-1R8 receptor signaling pathway, and alleviates DSS-induced colitis.