The 'cytokine storm': molecular mechanisms and therapeutic prospects

Abstract

Cytokine storm syndrome (CSS) has generally been described as a collection of clinical manifestations resulting from an overactivated immune system. Cytokine storms (CSs) are associated with various pathologies, as observed in infectious diseases, certain acquired or inherited immunodeficiencies and autoinflammatory diseases, or following therapeutic interventions. Despite the role of CS in tissue damage and multiorgan failure, a systematic understanding of its underlying molecular mechanisms is lacking. Recent studies demonstrate a positive feedback loop between cytokine release and cell death pathways; certain cytokines, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), can activate inflammatory cell death, leading to further cytokine secretion. Here, we discuss recent progress in innate immunity and inflammatory cell death, providing insights into the cellular and molecular mechanisms of CSs and therapeutics that might quell ensuing life-threatening effects.

Figure 1 |. Signaling pathways producing pro-inflammatory cytokines

a) The cartoon depicts the recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), RIG-I–like receptors (RLRs), or the cGAS-STING axis, engaging NF-κB, MAPK, and interferon regulatory factor 3 (IRF3)–IRF7 activation for the transcription of pro-inflammatory cytokine genes [42, 43, 89]. Fungal ligands bind the CLR dectin 1 and signal through the dectin 1–SYK pathway to activate NF-kB signaling. TLR signaling through MYD88 activates the NF-kB pathway, whereas TRIF-dependent TLR signaling primarily involves IRF3 and IRF7 activation. The depiction is based on results from human and murine studies. b) Inflammasome sensors can interact directly with their target ligand or respond to a variety of physiological changes. This leads to the recruitment of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and caspase 1 (CASP1) to form an inflammasome complex. CASP1 then undergoes proximity-induced autocatalytic cleavage to take on its active form. Activated CASP1 cleaves gasdermin D (GSDMD) to release the N-terminal domain, which oligomerizes in the plasma membrane and forms pores, thereby inducing cell death through pyroptosis. Activated CASP1 also cleaves pro–interleukin (IL)-1β and pro–IL-18 into their active forms, which are released through the GSDMD pores [43]. The depiction is based on results from human and murine studies. MAVS, mitochondria antiviral signaling; MDA5, melanoma differentiation-associated protein 5.

Figure 2 |. Regulation of inflammatory cell death by cytokines, cell death proteins, and infection

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.

Key Figure, Figure 3 |. Schematic representation of the mechanism of a cytokine storm

During pathogenic infections, autoinflammatory diseases, and other cytokine storm (CS)-inducing conditions, innate immune cells from humans and mice become activated and release multiple pro-inflammatory cytokines, including TNF and IFN-γ [16]. The synergistic response of TNF and IFN-γ can induce inflammatory cell death, which can result in more cytokines being produced and which might ultimately lead to a CS, with potential tissue and organ damage, and mortality in humans and mice [23]. Some components of Figure 3 were derived from BioRender.com.