IFI204-STING drives protective innate immunity against gangrenousinfection via regulation of NLRP3 signaling.

Abstract

Inflammasomes are an essential component of the innate immune response against pathogen infections. However, the molecular mechanism regulating the inflammasome signaling in response to gangrenous() infection remains elusive. We herein report the unexpected discovery that IFI204 (the murine homolog of human IFI16)-dependent STING protects againstgas gangrene via enhancing NLRP3 inflammasome signaling. In thegas gangrene model, compared with wild-type (WT) mice,deficiency () mice displayed an increased susceptibility tosoft tissue infection, with more bacterial colonization, severe muscle damage, and higher mortality rates. Obviously,deficiency leads to the defect of inflammasome signaling activation and bacterial killing and clearance. STING promotes inflammasome signaling activation in an IFI204-dependent manner. Crucially, the IFI204-STING axis enhances NLRP3 inflammasome signaling activation, which, in turn, facilitates pathogen elimination and host defense. Our findings highlight STING acts as a positive regulator in defense ofinfection and present it as a potential target for anti-infection drug development.