RIPK1 Distinctly Regulates Yersinia-Induced Inflammatory Cell Death, PANoptosis

Abstract

Bacterial pathogens from the genus Yersinia cause fatal sepsis and gastritis in humans. Innate immune signaling and inflammatory cell death (pyroptosis, apoptosis, and necroptosis [PANoptosis]) serve as a first line of antimicrobial host defense. The receptor-interacting protein kinase 1 (RIPK1) is essential for Yersinia-induced pyroptosis and apoptosis and an effective host response. However, it is not clear whether RIPK1 assembles a multifaceted cell death complex capable of regulating caspase-dependent pyroptosis and apoptosis or whether there is cross-talk with necroptosis under these conditions. In this study, we report that Yersinia activates PANoptosis, as evidenced by the concerted activation of proteins involved in PANoptosis. Genetic deletion of RIPK1 abrogated the Yersinia-induced activation of the inflammasome/pyroptosis and apoptosis but enhanced necroptosis. We also found that Yersinia induced assembly of a RIPK1 PANoptosome complex capable of regulating all three branches of PANoptosis. Overall, our results demonstrate a role for the RIPK1 PANoptosome in Yersinia-induced inflammatory cell death and host defense.

The ‘cytokine storm’: molecular mechanisms and therapeutic prospects

“…Genetic deletion of RIPK1 enhanced MLKL phosphorylation (necroptosis) but abrogated CASP1 and GSDMD cleavage (pyroptosis), and activation of CASP3 and CASP7 (apoptosis) during infection with Yersinia spp. [28]. However, the combined loss of CASP8, RIPK3, and CASP1 completely protected against Yersinia-induced cell death and cytokine release in murine macrophages [28], highlighting the essential role of PANoptosis in the cytokine-cell death positive-feedback loop.…”

“…For example, S. aureus releases αhemolysin and Hla, which activate necroptosis and pyroptosis via RIPK3 and NLRP3 signaling, resulting in increased inflammatory cytokine release and severe lung pathology in mice [87]. Similarly, Y. pestis, a causative agent of plague that has historically led to major pandemics, inactivates TAK1 with its effector protein YopJ, inducing cell death and inflammatory cytokine release in primary murine macrophages [28]. TAK1 is a prosurvival protein kinase that activates NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways downstream of Tolllike receptors (TLRs), the IL-1 receptor, and the TNF receptor, inducing the expression of several proinflammatory and prosurvival genes, many of which suppress the activation of CASP8-and RIPK1-dependent cell death in mammals [88] (Figure 2B).…”

“…Indeed, systemic inflammation, tissue damage, multiorgan failure, and mortality in CSS are prevented by combined treatments with TNF and IFN-γneutralizing antibodies, blocking cytokine-mediated inflammatory cell death in murine models of CSs [such as poly(I:C)-induced HLH, lipopolysaccharide (LPS)-induced sepsis, and SARS-CoV-2 infection] [23]. The identification of cell death-associated molecules, primarily caspase-8 (CASP8), Z-DNA-binding protein 1 (ZBP1), transforming growth factor-β-activated kinase (TAK1), and receptor-interacting serine/threonine protein kinase 1 (RIPK1), as master switches of inflammasome activation and of PCD pathways [24][25][26][27][28][29][30][31], has further established the concept of cytokine-mediated inflammatory cell death in infection, inflammatory disease, and cancer [32][33][34]. Understanding this cytokine-cell death positive feedback loop through which cytokines may cause inflammatory cell death to drive further cytokine release, CSs, organ damage, and lethality, is crucial for more effectively treating and possibly preventing CSS during diseases.…”

Inflammatory Cell Death, PANoptosis, Mediated by Cytokines in Diverse Cancer Lineages Inhibits Tumor Growth

“…Cancer is a group of diseases defined by abnormal growth of cells associated with pathological manifestations and significant morbidity and mortality globally (1). Because cancers are characterized by dysregulated cell death and inflammatory responses (24), many current therapeutic approaches aim to preferentially induce cell death in cancer cells (57). However, cancer cells acquire mutations that subvert the programmed cell death (PCD) pathways, making them refractory to anti-cancer therapies, and evasion of PCD mechanisms is one of the hallmarks of cancer (3).…”

Rabeprazole inhibits inflammatory reaction by inhibition of cell pyroptosis in gastric epithelial cells

“…Inflammasomes are multiprotein complexes that activate caspase-1, leading to maturation of the proinflammatory cytokines IL-1β and IL-18 and the induction of pyroptosis [14]. In general, intracellular pathogens was recognized by the NOD-like receptors (NLPs), especially NLR family pyrin domain containing 3 (NLRP3) to form NLRP3 inflammasome activation, which further activated caspase-1 [15]. The activation of caspase-1 cleaved gasdermin D (GSDMD), IL-1β and IL-18 into mature form, enabling cell membrane pore-formation for the release of IL-1β and IL-18 and triggering of pyroptosis [16].…”