Caspase-1 is known to function intracellularly. However, whether caspase-1 can be released extracellularly and if so, the mechanisms of its release and action remain unknown. Here, we identify that cleaved caspase-1 (p20), which we named extracellular caspase-1 (eCasp-1), is released from immune cells in association with gasdermin D (GSDMD) pores formation. We identified significantly elevated eCasp-1 levels in the blood of critically ill surgical ICU patients, and in the blood and peritoneal fluid of gut ischemia-reperfusion (I/R) injury mice. In vitro , hypoxia-reoxygenation promoted GSDMD-dependent eCasp-1 release, and pharmacological inhibition of GSDMD reduced this release, supporting a contributing role of GSDMD-mediated membrane permeabilization in eCasp-1 release. Gut I/R demonstrated robust GSDMD-dependent release of eCasp-1. Functionally, eCasp-1 engaged TLR4 on macrophages, eliciting robust inflammatory cytokine release and organ injury. Importantly, we developed a novel peptide, C16, designed to specifically inhibit the eCasp-1-TLR4 interaction. In gut I/R, C16 administration exerted therapeutic benefits, markedly reducing systemic inflammation, attenuating acute lung injury (ALI), and significantly improving the survival. Our findings identify eCasp-1 as a new alarmin, that contributes to ALI through TLR4 signaling, with GSDMD-dependent processes contributing to its extracellular release. Targeting eCasp-1 with C16 offers a promising therapeutic strategy against ALI in acute inflammation.
Ishikawa et al. (Wed,) studied this question.
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