Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4

Figures

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  Figure 1. It is now well-known that the myocardium is gradually damaged and develops into cardiac hypertrophy under chronic pressure overload. During the process, RAS and the sympathetic-adrenomedullary system are activated. With the progression of cardiac hypertrophy, the necrotic myocardium releases DAMPs, in which DAMPs and some PAMPs activate TLR4, and TLR4 subsequently activates the intracellular signaling pathways that promote the secretion of inflammatory mediators (e.g., inflammatory cytokines and chemokines). Immune cells migrate from the circulation to the heart in response to chemokines and then secrete pro-hypertrophic cytokines (e.g., TNF-α, IL-1β, and IL-6). In this context, upregulated cytokines expression can not only lead to cardiac hypertrophy, but also promote Ang II production by activating RAS, which also accelerates the development of cardiac hypertrophy and gives rise to cardiac dysfunction. Interestingly, the injured myocardium in turn produces some hypertrophic stimulus that can be recognized by TLR4. Therefore, there is a circulatory inflammatory loop that accelerates cardiac hypertrophy. In addition, prolonged exposure cytokines, especially TNF-α, impair the…

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  Figure 2. TLR4 signaling pathway: TLR4 is localized on the cell surface for ligand recognition, some of which are recognized after TLR4 interacting with MD2, even requiring CD14 and/or LBP involvement. Once activated by ligands on the cell surface, the TLR4/MD2 complex engage two separate downstream signaling pathways: the MyD88-dependent pathway and the TRIF-dependent pathway. The MyD88-dependent pathway mediates inflammatory response via some important transduction signaling such as NF-κB, PI3K/Akt, CaMK II, and MAPK, which promote NF-κB nuclear translocation and accelerate AP-1 transcriptional activation, and eventually leading to the secretion of inflammatory cytokines. In addition, there is crosstalk between MAPK and CaMK II signaling. TRIF plays an essential role in the MyD88-independent pathway through TLR4, type I IFNs are a crucial downstream molecule mediating hypertension and cardiac hypertrophy. Abbreviations: TLR4, Toll-like receptor 4; MD2, Myeloid differentiation protein 2; LBP, LPS binding protein; MyD88, Myeloid differentiation protein 88; TRIF, TIR-domain containing adaptor-inducing interferon-β; NF-κB, Nuclear factor-κB; PI3K/Akt, Phosphatidylinositol 3-kinase/Protein…

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  Figure 3. After cardiomyocytes are subjected to pathogenic stimulation, the TLR4 signaling pathway is activated to promote the secretion of chemokines and DAMPs, in which the upregulated expression of MCP-1 and ICAM-1 mediates the migration of macrophages and T cells from the circulation to the heart. Immune cells infiltrating the heart release inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which promote the development of cardiac hypertrophy. Meanwhile, resident macrophages and fibroblasts are also activated by DAMPs and release inflammatory cytokines in the early stage of inflammation. As the inflammation enters the late stage, cardiac fibroblasts differentiate into cardiac myofibroblasts, mediating cardiac repair and fibrosis. Importantly, cardiac fibroblasts and immune cells communicate with each other to regulate pro-inflammatory and pro-fibrotic effects. Abbreviations: TLR4, Toll-like receptor 4; DAMPs, Damaged associated molecular patterns; MCP-1, Monocyte chemoattractant protein-1; ICAM-1, Intercellular adhesion molecule-1; TNF-α, Tumor necrosis factor-α; IL-1β, Interleukin-1β; IL-6, Interleukin-6.