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

• Published in: The Journal of experimental medicine Vol. 217; no. 3
• Main Authors: Malireddi, R K Subbarao, Gurung, Prajwal, Kesavardhana, Sannula, Samir, Parimal, Burton, Amanda, Mummareddy, Harisankeerth, Vogel, Peter, Pelletier, Stephane, Burgula, Sandeepta, Kanneganti, Thirumala-Devi
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02.03.2020
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20191644

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.