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

TLDR

RIPK1 kinase activity is known to drive pyroptosis, apoptosis, and necroptosis. The study investigates a kinase‑activity‑independent role for RIPK1 in these cell death pathways using a TLR‑primed, TAK1‑deficient macrophage model. In TAK1‑deficient macrophages, TLR priming activates an inflammasome complex comprising caspase‑8, gasdermin D, NLRP3, and ASC that associates with RIPK1 independently of its kinase activity to trigger pyroptosis and apoptosis. The authors show that RIPK1 can mediate necroptosis via the RIPK3–MLKL pathway, and that TAK1 loss induces RIPK3–caspase‑8 signaling, myeloid proliferation, and a sepsis‑like syndrome, revealing a novel PANoptosis pathway that may be therapeutically targeted.

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.