The mammalian inhibitor of apoptosis proteins (IAPs) are key regulators of cell death and inflammation. A major function of IAPs is to block the formation of a cell death-inducing complex, termed the ripoptosome, which can trigger caspase-8-dependent apoptosis or caspase-independent necroptosis. Recent studies report that upon TLR4 or TNF receptor 1 (TNFR1) signaling in macrophages, the ripoptosome can also induce NLRP3 inflammasome formation and IL-1β maturation. Whether neutrophils have the capacity to assemble a ripoptosome to induce cell death and inflammasome activation during TLR4 and TNFR1 signaling is unclear. In this study, we demonstrate that murine neutrophils can signal via TNFR1-driven ripoptosome assembly to induce both cell death and IL-1β maturation. However, unlike macrophages, neutrophils suppress TLR4-dependent cell death and NLRP3 inflammasome activation during IAP inhibition via deficiencies in the CD14/TRIF arm of TLR4 signaling.
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Animals, Apoptosis, Caspases, Cell Death, Inflammasomes, Inflammation, Inhibitor of Apoptosis Proteins, Interleukin-1beta, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, Necrosis, Neutrophils, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Toll-Like Receptor 4, Tumor Necrosis Factors