Transcriptional regulation of macrophages in heart failure

Figures

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  Figure 1. Origin and function of cardiac macrophages. In the steady state, the heart contains a certain number of resident macrophages. According to the expression of C-C motif receptor-2 (CCR2), cardiac resident macrophages can be divided into CCR2− and CCR2+ macrophages. CCR2− resident macrophages are derived from embryonic yolk sac and fetal liver hematopoietic stem cells, which maintain their numbers by local proliferation. CCR2+ resident macrophages promote the recruitment of circulating monocytes mainly through the pathway of MyD88. The functions of CCR2− resident macrophages are facilitated cardiac electrical conduction, mitochondrial homeostasis, tissue repair, and adaptive myocardial remodeling. The functions of resident CCR2+ macrophages are proinflammatory response and type I interferon. During myocardial infarction, Ly6Chigh monocytes derived from the bone marrow and spleen are recruited to the infarct site under the action of chemokine CCL2, differentiate into recruited CCR2+ macrophages, and mediate inflammatory response. Subsequently, repairing Ly6Clow macrophages mediate repair response.

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  Figure 2. Regulation of recruited macrophage phenotypes and function in heart failure by transcription. Lgr4 promotes the transcription of Fos and Jun families through the cAMP/PKA/CREB pathway, synergistically increases the activity of AP-1, and promotes the downstream proinflammatory gene expression, thus aggravating cardiac inflammatory response and poor cardiac remodeling. YAP/TAZ binds to the proinflammatory cytokine IL-6 promoter, whereas YAP/TAZ inhibits Arg1 expression by binding to the Arg1 promoter and recruiting the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) inhibition complex. Lgr4/YAP loss of function has cardioprotective effects. MRTF-A in macrophages collaborates with transcription factor Sp1 and histone H3K9 demethylase KDM3A to promote integrin β2 (ITGB2) transcription, leading to an increase in the adhesion of macrophages to endothelial cells, eventually resulting in inflammatory response. Lactate transporter monocarboxylate transporter 1 (MCT1) provides abundant substrates for histone H3K18 lactylation (H3K18la) and promotes the repair genes Lrg1, Vegf-a, and IL-10 transcriptional. It is further found that histone acetyltransferase GCN5 is able…