GSDMD ablation reduces intestinal inflammation of experimental NEC through macrophage pyroptosis

Necrotizing enterocolitis (NEC) is predominantly linked to heightened macrophage inflammasome activity. This heightened activity triggers the pyroptotic cell death of macrophages, a process orchestrated by the protein gasdermin D (GSDMD). The exact contribution of macrophages pyroptosis to NEC remains to be fully elucidated. Our study delves into the pivotal function of GSDMD in the pyroptosis of macrophages within the context of experimental NEC. We identified a correlation between GSDMD and macrophage pyroptosis in the terminal ileum of infants with NEC. Employing GSDMD-deficient models and disulfiram, an agent that impedes GSDMD-mediated pore formation, we observed a marked improvement in the symptoms of NEC in mouse pups, coupled with a diminished presence of intestinal macrophages. Additionally, bone marrow-derived macrophages (BMDMs) from GSDMD-deficient mice demonstrated reduced overall macrophage numbers and M1 polarization. Notably, while GSDMD inhibition enhanced the macrophages antibacterial capabilities, their phagocytic activity towards zymosan particles was unaffected. Collectively, our findings highlight the integral role of GSDMD in modulating macrophage inflammasome responses and posit GSDMD as a promising candidate for therapeutic intervention in NEC.