Dextran sodium sulfate potentiates NLRP3 inflammasome activation by modulating the KCa3.1 potassium channel in a mouse model of colitis.

Bo Zeng, Yuanting Huang, Siyuan Chen, Rong Xu, Lihui Xu, Jiahao Qiu, Fuli Shi, Siying Liu, Qingbing Zha, Dongyun Ouyang, Xianhui He

Cellular & molecular immunology 2022 Aug

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Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, has increased in incidence and prevalence in recent decades. Both clinical and animal studies are critical for understanding the pathogenesis of this disease. Dextran sodium sulfate (DSS)-induced colitis is a frequently used animal model of IBD, but the underlying mechanism of the model remains incompletely understood. In this study, we found that NOD-like receptor family pyrin containing 3 (NLRP3) depletion markedly mitigated DSS-induced colitis and was accompanied by decreased activation of the inflammasome in the colons of mice. However, in vitro assays showed that DSS did not directly trigger but instead potentiated NLRP3 inflammasome assembly in macrophages in response to suboptimal ATP or nigericin stimulation. Mechanistically, DSS potentiated NLRP3 inflammasome activation in macrophages by augmenting KCa3.1-mediated potassium ion (K+) efflux. Furthermore, we found that pharmacologic blockade of the K+ channel KCa3.1 with TRAM-34 or genetic depletion of the Kcnn4 gene (encoding KCa3.1) not only ameliorated the severity of DSS-induced colitis but also attenuated in vivo inflammasome assembly in the colonic tissues of mice, suggesting a causal link between KCa3.1-mediated augmentation of the NLRP3 inflammasome and DSS-induced inflammatory injuries. Collectively, these results indicate that KCa3.1 plays a critical role in mediating DSS-induced colitis in mice by potentiating NLRP3 inflammasome activation. Our data provide a previously unknown mechanism by which DSS induces colitis in mice and suggests that KCa3.1 is an alternative therapeutic target for treating IBD. © 2022. The Author(s), under exclusive licence to CSI and USTC.

Citation

Bo Zeng, Yuanting Huang, Siyuan Chen, Rong Xu, Lihui Xu, Jiahao Qiu, Fuli Shi, Siying Liu, Qingbing Zha, Dongyun Ouyang, Xianhui He. Dextran sodium sulfate potentiates NLRP3 inflammasome activation by modulating the KCa3.1 potassium channel in a mouse model of colitis. Cellular & molecular immunology. 2022 Aug;19(8):925-943