TNF switches homeostatic efferocytosis to lytic caspase-8-dependent pyroptosis and IL-1β maturation

Efferocytosis, wherein phagocytes engulf dead or dying cells, is a critical function of macrophages that supports cellular turnover, tissue repair, and resolution of inflammation. Despite its well-established anti-inflammatory mechanism in homeostasis, whether efferocytosis remains immunologically silent in the context of dysregulated immune responses such as sepsis or systemic inflammatory response syndrome (SIRS) has not been investigated. Here, we used mouse models of tumor necrosis factor (TNF)-induced SIRS and Escherichia coli-induced septic peritonitis to uncover a potential negative consequence of efferocytosis. We found that when activated with TNF, phagocytes efferocytosing neutrophils initiated a caspase-8-dependent, but NLRP3 inflammasome-independent, form of pyroptosis, which we termed "efferoptosis." The maturation of IL-1β, a hallmark of pyroptotic cell death, also occurred independently of canonical inflammasome activation, supporting direct cleavage by caspase-8. Inhibition of efferocytosis protected mice against TNF-induced SIRS, suggesting that efferoptosis contributes to the pathology of sepsis and other TNF-mediated inflammatory conditions.