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Summary: Blockade of programmed cell death 1 (PD-1) is considered a promising strategy for controlling pathogen infection by enhancing host immune cell function. Eosinophils, which play a crucial role in type 2 immune responses, are essential components of the host defense against helminth infection. Here, we investigate the role of PD-1 in eosinophilia during Trichinella spiralis infection in mice. PD-1-deficient (PD-1−/−) mice exhibit delayed expulsion of adult worms and increased muscle larva burdens compared to wild-type mice following infection. Additionally, PD-1−/− mice display impaired recruitment of eosinophils to parasite-invaded tissues, attributed to decreased upregulation of adhesion molecules on both eosinophils and vascular endothelium after infection. The compromised Th2 cytokine response further contributes to impaired adhesion interactions, affecting eosinophil migration and cytotoxicity against larvae in vitro within T. spiralis-infected PD-1−/− mice. Our findings demonstrate a positive role for PD-1 in the recruitment of eosinophils, suggesting its involvement in host defense against helminth infection.

Summary: cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1−/− BMDM cells and in Trex1−/− mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases. : Li et al. have characterized a small-molecule cyclopeptide, astin C, which specifically inhibits cGAS-STING signaling as well as the innate inflammatory responses. This finding provides a way to potentially manipulate STING-mediated clinical diseases. Keywords: cGAS, STING, IRF3, TBK1, HSV-1, cyclopeptide, astin C, therapeutic target, innate immunity, autoimmune diseases