Potential Pathophysiological Mechanisms Underlying Multiple Organ Dysfunction in Cytokine Release Syndrome

Figure 2

Cytokine signaling pathway activated by IL-6, TNF-α, IFN-γ, IL-1, and the inflammasome. (a) IL-6 mainly mediates signal transduction through Ras-Raf-ERK-MAPK, NF-κB, JAK/STAT3, and PI3K-Akt-mTOR. (b) IFN-γ activates the downstream pathway through JAK/STAT1 and NF-κB to generate a cascade amplification effect. (c) TNF-α promotes inflammatory response diffusion through NF-κB activation (activated by the sequential recruitment of TRAF2, RIP, TAK1, and IKK) and induces apoptosis by activation of AP-1 and caspase-3. After recruitment of TRAF2 and RIP, AP-1 can be activated through three pathways, in which the following key molecules are involved: ① MEKK and JNK, ② P38a, and ③ ERK and MAPK. Caspase-3 levels can be elevated by sequential recruitment of TRADD, FADD, and caspase-8 or via TRADD, ROS, and caspase-9. (d) IL-1 decomposes into IL-1α and IL-1β under inflammasome activation, and then, IL-1β is released through Gasdermin D (GSDMD) lysate pore and induces cell swelling and apoptosis. The first and second signals are necessary for activation of the inflammasome. JAK: Janus kinase; STAT: the signal transducer and activator of transcription; Ras: a GTPase; Raf: Raf kinase; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; SHP2: Src homology 2-containing protein tyrosine phosphatase 2; PI3K: phosphatidylinositol 3 kinase; AKT: protein kinase B (PKB); mTORC1: mammalian target of rapamycin complex 1; TRAF2: TNFR-associated factor 2; RIP: receptor-interacting protein; TAK1: TGF-β-activated kinase 1; TGF-β: transforming growth factor-β; IKK: inhibitor of κB kinase; MEKK: MAP/ERK kinase kinase; JNK: c-Jun N-terminal kinase; p38a: p38 mitogen-activated protein kinase; AP-1: activator protein-1; TRADD: TNFR-associated death domain; FADD: Fas-associated protein with death domain; NLRP3: NOD-like receptor (NLR) protein 3; ASC: adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain; caspase: cysteinyl aspartate specific proteinase.