NLRP6/NLRC4/ASC and cGAS/STING Pathways Drive Non-Canonical Inflammasome Activation in Natterin-induced Neutrophilic Inflammation

Using a combination of pharmacologic and genetic loss-of-function approaches we conduct a systematic investigation of the regulatory mechanisms that control Natterin-induced neutrophilic inflammation in the peritonitis model. We found that neutrophil recruitment is mediated by signals derived from IL-33/ST2 and IL-1/IL1R dependent on caspase-11/1 produced by epithelial cells. Neutrophilia induced by Natterin is dependent on gasdermin-D, independently of pyroptosis. Interestingly, this non-canonical inflammasome depends on cytosolic Natterin recognition by NLRP6/NLRC4/ASC complex and activation of cGAS/STING/IRF3 pathway by dsDNA, which drives the type I/III IFNs signaling. The biological significance of our findings is the application of pharmacological inhibitors of cGAS/STING signaling for the treatment of ischemic injury caused by venomous T. nattereri fish, which Natterin plays a decisive role in its development.