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TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation

R. Malireddi,Prajwal Gurung,J. Mavuluri,T. Dasari,J. Klco,H. Chi,T. Kanneganti

Published 2018 in Journal of Experimental Medicine

ABSTRACT

The NOD-like receptor (NLR)–P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-&bgr; activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis. Autocrine tumor necrosis factor (TNF) signaling in the absence of TAK1 induced spontaneous RIPK1-dependent NLRP3 inflammasome activation and cell death. We further showed that TAK1 suppressed homeostatic NF-&kgr;B and extracellular signal–related kinase (ERK) activation to limit spontaneous TNF production. Moreover, the spontaneous inflammation resulting from TAK1-deficient macrophages drives myeloid proliferation in mice, and was rescued by RIPK1 deficiency. Overall, these studies identify a critical role for TAK1 in maintaining NLRP3 inflammasome quiescence and preserving cellular homeostasis and survival.

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