Blockade of IAPs Sensitizes Neutrophils to TNF- but Not LPS-Mediated Cell Death and IL-1β Secretion

The Inflammasome Lab have discovered that neutrophils can signal via TNFR1-driven ripoptosome assembly to induce both cell death and IL-1β maturation, but suppress TLR4-dependent cell death and NLRP3 inflammasome activation during IAP inhibition, via deficiencies in the CD14/TRIF arm of TLR4 signaling. This discovery is now published as a Cutting Edge article in the Journal of Immunology.

 

Chen KW, Lawlor KE, von Pein JB, Boucher D, Gerlic M, Croker BA, Bezbradica J, Vince JE, Schroder K. (2018).
Cutting edge: IAP inhibition sensitizes neutrophils to TNF but not LPS-mediated cell death and IL-1β secretion. Journal of Immunology In press. Pubmed

 

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.

 

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ABOUT Inflammasome Lab

Inflammasome Lab is a group of researchers led by Dr Kate Schroder at the Institute for Molecular Bioscience, The University of Queensland.
We seek to unravel the secrets of inflammasomes – protein complexes at the heart of inflammation and disease – to allow for new therapies to fight human diseases.