The ＇cytokine storm＇: molecular mechanisms and therapeutic prospects

a) Schematic representation of inflammatory cell death induced by the combination of TNF and IFN-γ. Activation of JAK–STAT1 signaling by TNF and IFN-γ induces the upregulation of interferon regulatory factor 1 (IRF1), which in turn triggers upregulation of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO). NO then leads to caspase 8 (CASP8) activation. Activated CASP8 induces gasdermin E (GSDME)-mediated pyroptosis, caspase-3 and caspase-7 (CASP3 and CASP7)-driven apoptosis and RIPK3 and mixed lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis [23]. The depiction is based on results from human and murine studies. b) TNF stimulation induces rapid assembly of a multiprotein signaling complex containing TNF receptor type 1 (TNFR1)-associated DEATH domain protein (TRADD) and receptor interacting protein kinase 1 (RIPK1), which subsequently recruits E3 ubiquitin ligases such as cIAP1/2 and LUBAC [99, 100]. The K63-linked ubiquitin chains generated by cIAP1/2 induce transforming growth factor β-activated kinase 1 (TAK1) recruitment and RIPK1 phosphorylation. LUBAC further conjugates the RIPK1 complex with M1linked linear ubiquitin chains [100]. The deubiquitinase A20 mediates the cleavage of K63-linked ubiquitin chains on RIPK1. Furthermore, A20 can add K48-linked ubiquitin chains to RIPK1, thereby targeting it for proteasomal degradation [101]. The phosphorylation of RIPK1 by IKKα– IKKβ, TBK1–IKKε and TAK1 maintains its prosurvival signaling [88]. Inhibition of RIPK1 phosphorylation dissociates RIPK1 from the TNFR1 complex and triggers its assembly with Fas-associated death domain protein (FADD) and CASP8, which triggers gasdermin D (GSDMD) and GSDME-mediated pyroptosis and CASP3–CASP7–mediated apoptosis [83]. Inhibition of CASP8 induces RIPK1 to phosphorylate RIPK3, thereby triggering MLKL-mediated necroptosis. The depiction is based on results from human and murine studies. c) Influenza A virus (IAV) Z-RNA is recognized by the Zα2 domain of Z-DNA binding protein 1 (ZBP1) [25, 93]. Caspase-6 (CASP6) promotes the interaction between ZBP1 and RIPK3 [92]. ZBP1 triggers NLRP3-dependent GSDMD cleavage, CASP8-dependent CASP3 and CASP7 activation, and MLKL phosphorylation to induce inflammatory cell death during IAV infection [25]. The depiction is based on results from murine studies. ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; CARD, caspase recruitment domain; DD, death domain; DED, death effector domain; FADD, fas-associated death domain protein; LRR, leucine-rich repeat; RHIM, receptor interacting protein homotypic interaction motif.
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