Gasdermin E (GSDME) regulates inflammatory responses by controlling the mode of neutrophil death. Neutrophils, short-lived cells, undergo programmed cell death (PCD) through either lytic (e.g., pyroptosis) or anti-inflammatory (apoptosis) pathways. GSDME, a gasdermin family member, is cleaved and activated in aging neutrophils, leading to pyroptosis. GSDME deficiency prevents pyroptosis and shifts neutrophil death toward apoptosis, enhancing efferocytosis by macrophages and reducing inflammation. In a clinically relevant acid-aspiration-induced lung injury model, GSDME deletion reduced inflammation and lung injury. GSDME is cleaved by proteinase-3 and caspase-3 during neutrophil aging, leading to lytic death. GSDME disruption skews neutrophil death to apoptosis, increasing efferocytosis and anti-inflammatory responses. In peritonitis and LPS-induced lung injury models, GSDME deficiency reduced inflammatory cytokines (e.g., IL-1β) and neutrophil accumulation, alleviating tissue damage. Neutrophil-specific GSDME deletion enhanced efferocytosis, reducing inflammation and lung injury. GSDME also plays a role in modulating immune responses in S. aureus-induced pneumonia, where it reduced pro-inflammatory cytokines and bacterial burden without compromising bacterial clearance. Overall, GSDME controls neutrophil death mode, influencing host inflammatory outcomes and offering therapeutic potential for infectious and inflammatory diseases.Gasdermin E (GSDME) regulates inflammatory responses by controlling the mode of neutrophil death. Neutrophils, short-lived cells, undergo programmed cell death (PCD) through either lytic (e.g., pyroptosis) or anti-inflammatory (apoptosis) pathways. GSDME, a gasdermin family member, is cleaved and activated in aging neutrophils, leading to pyroptosis. GSDME deficiency prevents pyroptosis and shifts neutrophil death toward apoptosis, enhancing efferocytosis by macrophages and reducing inflammation. In a clinically relevant acid-aspiration-induced lung injury model, GSDME deletion reduced inflammation and lung injury. GSDME is cleaved by proteinase-3 and caspase-3 during neutrophil aging, leading to lytic death. GSDME disruption skews neutrophil death to apoptosis, increasing efferocytosis and anti-inflammatory responses. In peritonitis and LPS-induced lung injury models, GSDME deficiency reduced inflammatory cytokines (e.g., IL-1β) and neutrophil accumulation, alleviating tissue damage. Neutrophil-specific GSDME deletion enhanced efferocytosis, reducing inflammation and lung injury. GSDME also plays a role in modulating immune responses in S. aureus-induced pneumonia, where it reduced pro-inflammatory cytokines and bacterial burden without compromising bacterial clearance. Overall, GSDME controls neutrophil death mode, influencing host inflammatory outcomes and offering therapeutic potential for infectious and inflammatory diseases.