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. 2021 May 27;13(6):1003. doi: 10.3390/v13061003

Figure 3.

Figure 3

Proposed roles of Toll-like receptors in viral myocarditis. Every phase of the myocarditis disease process has several associations with Toll-like receptors (TLRs), although for some the evidence is limited. These include aspects where TLRs are considered beneficial (green plane) as well as elements where TLRs potentially confer harm to the host (red plane). The ratio between both aspects determines the overall impact of TLRs on the disease process, as indicated by the weighing balance. Phase 0: TLR sex differences have been put forward as explanation for the sex bias in viral myocarditis (in which the female sex offers protection). The impact of sex hormones could run through TLR modulation. Genetic differences in TLRs are among the factors that influence host susceptibility to viral myocarditis. Phase 1: TLRs can induce autophagy and viruses can use autophagosomes as a platform for their replication. MyD88 impacts expression of CAR, an important viral receptor. MAPK family members seem to have a role in CVB replication and apoptosis regulation. Activation of MAPK pathways leads to intracellular calcium mobilisation during viral replication, contributing to cell death. Phase 2: TLRs are central in innate and adaptive immune system activation in response to the offending virus. Inappropriate TLR activation by self-components propagates sterile inflammation and contributes to the development of autoimmunity. Phase 3: The inflammatory response promotes and coordinates the repair phase that follows the cardiac insult. A feedback loop between extracellular matrix (ECM) constituents and TLRs is suggested in which ECM molecules act as DAMPs and subsequent TLR activation affects the ECM. Besides sterile inflammation, ECM-mediated activation of TLRs could also cause other negative consequences, for example stimulation of fibrogenesis. In all phases, TLR activation can negatively affect cardiomyocyte contractility. Abbreviations: AP, autophagosome; CAR, coxsackievirus-adenovirus receptor; CVB, coxsackie B virus; ECM, extracellular matrix; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response gene 88; SNP, single-nucleotide polymorphism; TLR, Toll-like receptor.