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

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

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

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.

Original languageEnglish (US)
Article numbere20191644
JournalJournal of Experimental Medicine
Volume217
Issue number3
DOIs
StatePublished - Mar 2 2020
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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