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The NLRP3 inflammasome plays a critical role in the innate immune response, and its excessive activation will cause pyroptotic cell death and be associated with the onset of inflammatory diseases. However, NLRP3 inflammasome targeting therapies are still to be implemented in the clinic setting. Here, we first isolated, purified and characterized a novel Vitenegu acid from V. negundo L. herb that specifically inhibits NLRP3 inflammasome activation, without affecting NLRC4 or AIM2 inflammasomes. Vitenegu acid blocks the oligomerization of NLRP3, thus inhibiting NLRP3 inflammasome assembly and activation. In vivo data show that Vitenegu acid exerts therapeutic effects on NLRP3 inflammasome-dependent inflammation. Taken together, our results suggest that Vitenegu acid is a candidate therapeutic agent for treating NLRP3 inflammasome related diseases.

The NLRP3 inflammasome is involved in a diverse range of inflammatory diseases. The activation of inflammasomes must be tightly regulated to prevent excessive inflammation, and the protein ubiquitination system is reported to be one of the ways in which inflammasome activation is regulated. However, the deubiquitination regulatory mechanisms of inflammasome activation remain elusive. Here, we demonstrated that USP22 (ubiquitin specific peptidase 22) promotes NLRP3 degradation and inhibits NLRP3 inflammasome activation. USP22 deficiency or in vivo silencing significantly increases alum-induced peritonitis and lipopolysaccharide-induced systemic inflammation. Mechanistically, USP22 inhibits NLRP3 inflammasome activation via the promotion of ATG5-mediated macroautophagy/autophagy. USP22 stabilizes ATG5 via decreasing K27- and K48-linked ubiquitination of ATG5 at the Lys118 site. Taken together, these findings reveal the role USP22 plays in the regulation of NLRP3 inflammasome activation and suggest a potential therapeutic target to treat NLRP3 inflammasome-related diseases. Abbreviations: ATG5: autophagy related 5; ATP: adenosine triphosphate; CASP1: caspase 1; IL18: interleukin 18; IL1B/IL-1β: interleukin 1 beta; LPS: lipopolysaccharide; NLRC4: NLR family, CARD domain containing 4; NLRP3: NLR family, pyrin domain containing 3; PYCARD/ASC: PYD and CARD domain containing; TNF/TNF-α: tumor necrosis factor; USP22: ubiquitin specific peptidase 22.

Inflammatory bowel diseases (IBDs) are increasingly common diseases characterized by chronic and relapsing inflammation of the gastrointestinal tract. NLRP3 might be a crucial regulator of the homeostatic balance of the intestine, but its upregulation leads to pyroptosis. Munronoid I is extracted and purified from Munronia sinica, which has shown an anti-inflammatory effect, but the efficacy of Munronoid I in IBD remains unproven. In this study, we attempted to determine the effect of Munronoid I on NLRP3 to regulate the inflammasome activation and pyroptosis in IBD. Our data demonstrated that Munronoid I treatment attenuated DSS-induced body weight loss, pathological injury of the colon, the production of IL-1β and IL-18, and the expression of pyroptosis-associated proteins in colon tissue in mice. Moreover, Munronoid I inhibited LPS/ATP-induced pyroptosis in mouse peritoneal macrophages, MODE-K cells, and DSS-induced pyroptosis in mouse colonic epithelial cells, and decreased the release of inflammatory cytokines IL-1β and IL-18 in mouse peritoneal macrophages. Mechanically, Munronoid I could suppress the NLRP3 inflammasome activation and pyroptosis by promoting the K48-linked ubiquitination and NLRP3 degradation. It is suggested that Munronoid I might be a potential therapeutic candidate for IBD.

Inflammatory bowel diseases (IBDs) are increasingly common diseases characterized by chronic and relapsing inflammation of the gastrointestinal tract. NLRP3 might be a crucial regulator of the homeostatic balance of the intestine, but its upregulation leads to pyroptosis. Munronoid I is extracted and purified from