Abstract Gasdermins(GSDMs)-mediated pyroptosis has been extensively visualized in vitro and linked to multiple physiological and pathological processes. However, the in vivo phenotype and clinical outcome of pyroptosis remain undetermined. Here, we sought to profile the in vivo pyroptosis using lipid-nanoparticle (LNP)-capsulated mRNA encoding the pore-forming N-terminal of GSDMD (GSDMDNT). Upon intravenous injection, robust expression of GSDMDNT led to acute liver damage, systemic inflammation, and sudden death both in mice and non-human primates, which could be reverted by the GSDMD inhibitor disulfiram or glucocorticoids. Imaging techniques revealed that GSDMDNT targeted both plasma membrane and intracellular membranous organelles, causing membrane rupture, organelle swelling, as well as the formation of intracellular membranous vacuoles. Furthermore, heterologous expression of other GSDM members also caused pyroptosis both in vitro and in vivo with varying magnitude. These findings provide insights into the dynamic characteristic of pyroptotic organ injury-related diseases and offer the basis for developing GSDM-based therapeutics.
Huang et al. (Tue,) studied this question.
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