Innate Immune Priming in the Absence of TAK1 Drives RIPK1 Kinase Activity-independent Pyroptosis, Apoptosis, Necroptosis, and Inflammatory Disease

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2019 Dec 24

PMID 31869420

Citations 156

Authors

R K Subbarao Malireddi

Prajwal Gurung

Sannula Kesavardhana

Parimal Samir

Amanda Burton

Harisankeerth Mummareddy

Peter Vogel

Stephane Pelletier

Sandeepta Burgula

Thirumala-Devi Kanneganti

Affiliations

Soon will be listed here.

Abstract

RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity-independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity-independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity-independent necroptosis driven by the RIPK3-MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3-caspase-8 signaling axis-driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity-independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.

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