1. Cutting Edge: Blockade of Inhibitor of Apoptosis Proteins Sensitizes Neutrophils to TNF- but Not Lipopolysaccharide-Mediated Cell Death and IL-1β Secretion
- Author
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Kaiwen W. Chen, Jelena S. Bezbradica, Dave Boucher, Jessica B. von Pein, Kate E. Lawlor, Ben A. Croker, James E Vince, Motti Gerlic, and Kate Schroder
- Subjects
Lipopolysaccharides ,0301 basic medicine ,Programmed cell death ,Inflammasomes ,Neutrophils ,Necroptosis ,Interleukin-1beta ,Immunology ,Ripoptosome ,Apoptosis ,Inhibitor of apoptosis ,Inhibitor of Apoptosis Proteins ,Mice ,Necrosis ,03 medical and health sciences ,0302 clinical medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Immunology and Allergy ,Inflammation ,Cell Death ,Chemistry ,Macrophages ,Inflammasome ,Cell biology ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,030104 developmental biology ,Receptors, Tumor Necrosis Factor, Type I ,Caspases ,Tumor Necrosis Factors ,Tumor necrosis factor alpha ,Signal transduction ,Ripoptosome assembly ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
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.
- Published
- 2018