Figure 1.

The possible mechanisms underlying the cytokine release syndrome induced by IL-6 elevation in COVID-19 patients. In severe patients infected with SARS-Cov-2, antigen-presenting cells (e.g., dendritic cells and monocytes) demonstrated low interferon response while maintaining pro-inflammatory cytokines production. Besides, the count of CD4+ T cells and CD8+ T cells also decreased in severe COVID-19 cases. The impaired anti-viral responses resulted in delayed viral clearance and massive viral replication, leading to persistent production of pro-inflammatory cytokine (e.g., IL-1β, IL-6, TNF-α). A large amount of IL-6 was secreted by non-immune cells upon stimulation of IL-6 through trans-signaling, which formed a positive feedback or so-called “inflammation amplifier.” The “amplifier” resulted in the surge in pro-inflammatory cytokines and chemokines (IL-6, IL-1β, IP-10, IL-2, IL-10, IFNγ, MCP1, GM-CSF, TNF.), contributing to the development of cytokine release syndrome and the recruitment of inflammatory cells, including monocytes, neutrophils, and macrophage cells. The infiltrates of inflammatory cells in lung led to acute respiratory dysfunction syndrome and the exacerbation of the COVID-19. MYD88, myeloid differentiation primary response 88; IRAK1-4, IL-1R-associated kinase family kinase 1-4; TRAF6, tumor necrosis factor receptor-associated factor 6; TAB 2/3, TGF-β-activated kinase 1-binding protein 2/3; TAK1, TGF-β-activated kinase 1; NEMO, NF-κB essential modulator; IFN, interferon; IL-6, Interleukin-6; GP130, glycoprotein 130; IL-6R, Interleukin-6 receptor; ADAM17, ADAM metallopeptidase domain 17; ARDS, acute respiratory distress syndrome.