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. 2020 Jul 10;11:1708. doi: 10.3389/fimmu.2020.01708

Figure 1.

Figure 1

Artemisinin-family drugs for cytokine storm in COVID-19. The dysregulation of the cytokine storm involves mainly APCs. TLR2 and TLR4 locate mainly outside macrophages, DCs, and granulocytes. Also, they are expressed within endosomes, play a role in recognizing bacteria and viruses. Through MyD88-dependent or TRIF-dependent pathway, TLR2 and TLR4 transmit signals for the activation of IRF3 and NF-κB to induce the type I interferon and cytokines. Besides, TLR2 leads to the activation of AP-1, which is responsible for the transcription of inflammatory cytokines. The cytokines target at the naïve T helper cell, to result in the naïve T helper cell to differentiate to Th1 cell and Th17 cell, subsequently to secrete the inflammatory cytokines and chemokines. Moreover, the IL-6, IL-8, and IL-10 secreted by monocytes and macrophages could activate cytokines receptors (i.e., IL-6R, IL-8R), lead to the activation of JAK-STAT signaling pathways and cell migration. The artemisinin-family drugs target at a variety of molecules (red and blueness nodes) in the inflammatory networks, such as NF-κB, IRF3, ERK (not shown in the figure), and RORγt, which inhibit the differentiation of inflammatory cells and the production of cytokines and chemokines. IL-10 is an anti-inflammatory cytokine. It could be secreted by virtually all immune cells, including macrophages, DCs, NK cells, T cells, and B cells. At the moment, the high concentration of IL-10 in severely ill patients with COVID-19 is a mystery. On the one hand, it might play a role in antagonizing the biological function induced by IL-6. On the other hand, the high concentration of IL-10 might contribute to the lymphocytes exhaustion. AP-1, activating protein-1; CCL, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand; IKK, IκB kinase; IFN, interferon; IRF3, interferon response factor 3; JAK, Janus kinase; JNK, Jun N-terminal kinase; MyD88, myeloid differentiation primary response protein 88; NF-κB, Nuclear factor κ B; NLPR3, NOD-, LRR- and pyrin domain-containing protein 3; MKK, Mitogen-activated protein kinase kinase; SMAD5, SMAD Family Member 5; RORγt, retinoic acid receptor-related orphan nuclear receptor gamma t; STAT, Signal transducer and activator of transcription; TAK1, TGFβ-activated kinase; T-bet, T-box transcription factor 21 (also known as TBX21); TLR, Toll-like receptor; TRAF, TNF receptor-associated factor; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain–containing adaptor protein inducing interferon-β. IL, interleukin.