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Title: Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease.

Authors: Malireddi, R K Subbarao; Gurung, Prajwal; Kesavardhana, Sannula; Samir, Parimal; Burton, Amanda; Mummareddy, Harisankeerth; Vogel, Peter; Pelletier, Stephane; Burgula, Sandeepta; Kanneganti, Thirumala-Devi

Published In J Exp Med, (2020 03 02)

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.

PubMed ID: 31869420 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/immunology*; Caspase 8/immunology; Female; Immunity, Innate/immunology*; Inflammasomes/immunology; Inflammation/immunology*; MAP Kinase Kinase Kinases/immunology*; Macrophages/immunology; Mice; Mice, Knockout; Necroptosis/immunology*; Pyroptosis/immunology*; Receptor-Interacting Protein Serine-Threonine Kinases/immunology*; Signal Transduction/immunology

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