Role of Toll-Like Receptors and Th Responses in Viral Myocarditis

Figures

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  Figure 1. Differentiation of naïve CD4+T cells. Naive CD4+T cells can differentiate into Th1 cells under the stimulus of IFN-γ and IL-2, secrete IFN-γ, IL-2, and TNF, and participate in type 1 immune response. Under the stimulus of IL-2 and IL-4, naive CD4+T cells differentiate into Th2 cells that can secrete IL-4/5/6/10/13 and participate in type 2 immune response. The differentiation of Th17 cells need TGF-β, IL-6, IL-21, and IL-23, and participate in type 3 immune response through secreting IL-17/17F/21/22; TGF-β and IL-2 are required for naïve CD4+T cells to differentiate into Treg cells that secrete IL-10 and TGF-β regulate the immune response.

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  Figure 2. TLRs signaling pathway and related Th responses. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are expressed on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are expressed on intracellular vesicles. TLRs can recognize different ligands and recruit adapter proteins, MyD88, Mal, TRIF, or TRAM, activating the downstream signaling pathway. TLR10 is an orphan receptor and lacks a classical downstream signaling pathway. Some TLRs promote the differentiation of Th cells. TLR2/6 promotes Treg cell differentiation through the JNK pathway. TLR2/1 promotes Th1 and Th17 cell differentiation through p38 MAPK pathway. TLR4 eliminates the Th1 response through IRF1 and promotes Th17 cell differentiation by STAT3 pathway. TLR5 can stimulate the body to induce Th2 response, inhibit Th1 response, and promote DC differentiation into Th17 cells. TLR8 induces the expression of IL-12B and IL-23A, promotes the differentiation of IL-23-dependent Th17 cells. TLR9 promotes the differentiation of Th1 cells. Green lines: TLR signaling pathways; black lines: TLRs related to Th cell differentiation; red lines: co-stimulation of TLRs induced to Th1 cell.

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  Figure 3. Myocarditis and Th responses. An imbalance of Th cells is observed in the pathogenesis of myocarditis. Th1 and Treg cells are predominant in the acute phase of myocarditis, while Th2 and Th17 cells dominate the chronic phase of myocarditis. Some drugs regulate the balance of Th cells in myocarditis. (A) Atorvastatin; (B) Tanshinone IIA; (C) Apigenin; (D) Cyclooxygenase-2 inhibitors; (E). Valproic acid; (F) Fenofibrate.

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  Figure 4. TLR signaling pathway related to CVB3 infection. TLR4/NF-κB is activated after CVB3 infection; TLR3 recognizes CVB3 dsRNA and activates TRIF and TRAF6 to transmit signals to NF-κB; TLR8 recognizes CVB3 ssRNA and activates NF-κB signaling pathway. TLR2 and TLR8 recognizes HCM and promotes the differentiation of Th cells. Although other TLRs may be related to the pathogenesis of myocarditis, whether other TLRs can be activated and its downstream pathway after CVB3 infection has not been reported.