GSDMD deficiency mitigates intestinal damage via macrophage pyroptosis control in experimental NEC.

Abstract

Necrotizing enterocolitis (NEC) is primarily associated with an intensified inflammatory response within macrophage inflammasomes. This increased activity initiates pyroptotic cell death in macrophages, a process meticulously regulated by the protein gasdermin D (GSDMD). The precise role of macrophage pyroptosis in NEC is yet to be comprehensively understood. Our research explores the critical role of GSDMD in macrophage pyroptosis during experimental NEC. We have discovered a significant correlation between GSDMD and macrophage pyroptosis in the terminal ileum of infants afflicted with NEC. By utilizing GSDMD-deficient models and disulfiram, a compound that disrupts GSDMD-mediated pore formation, we observed a significant alleviation of NEC symptoms in mouse pups, along with a reduced presence of intestinal macrophages. Furthermore, bone marrow-derived macrophages (BMDMs) from GSDMD-deficient mice showed a decrease in overall macrophage numbers and a shift away from M1 polarization. Interestingly, although GSDMD inhibition bolstered the antibacterial capabilities of macrophages, their phagocytic activity towards zymosan particles remained unchanged. In summary, our findings underscore the essential function of GSDMD in regulating macrophage inflammasome responses and suggest that GSDMD could serve as a potential therapeutic target for NEC.