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

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.

Toward targeting inflammasomes: insights into their regulation and activation

“…The unveiling of ZBP1 and TAK1 as master regulators of pyroptosis, apoptosis, and necroptosis, along with the rapidly expanding evidence of communication between these pathways, has led to the concept of PANoptosis, in which a putative PANoptosome acts as a central cell death complex that can initiate all three of these pathways. 151,152 The convergence of these three programmed cell death pathways and the identification of master regulators controlling all three is intriguing and could be powerful therapeutically. Future research will be needed to determine the therapeutic potential of these master regulators and to unravel the complexities of this central PANoptotic process, including detailed exploration of the mechanisms of this multifaceted cell death.…”

Therapeutic modulation of inflammasome pathways

“…55 TAK1 inhibition and a host of additional microbial pathogens also induce NLRP3 inflammasome-mediated pyroptosis concomitant with induction of necroptosis and extrinsic apoptosis in the targeted cell population, a process that was recently coined as PANoptosis. [56][57][58][59] Moreover, gain-of-function mutations in NLRP3 cause autosomal dominantly inherited autoinflammatory diseases that are collectively named Cryopyrin-Associated Periodic Syndrome (CAPS), and which comprise-in increasing order of clinical severity-familial F I G U R E 1 Overview of different inflammasome complexes: (From left to right) Engagement of different TLR receptors leads to activation of IKKs, which in turn results in activation of NF-κB signaling. Consequently, NF-κB upregulates different pro-inflammatory cytokines such as TNF, IL-6, and pro-IL-1β.…”

Cross talk between intracellular pathogens and cell death

“…In this new complex (the necrosome), RIPK3 is believed to undergo autoactivation and further phosphorylates the pseudokinase mixed lineage kinase domain‐like protein (MLKL) to execute necroptotic death. Interestingly, in TAK1‐deficient cells, TLR stimulation appears to trigger the assembly of Complex II, which is able to trigger a mixture of apoptosis, pyroptosis, and necroptosis, dubbed as “PANoptosis” 85 . A recent study revealed that several enteric pathogens including enterohemorrhagic Escherichia coli (EHEC), EPEC, and C. rodentium encode a novel bacterial cysteine protease, EspL which cleaves RHIM‐containing adaptor proteins such as RIPK1, RIPK3, TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF), and Z‐DNA‐binding protein 1 (ZBP1) to that are associated with both apoptotic and necroptotic signaling 67 .…”