M2 macrophage-derived paracrine factor TNFSF13 affects the fibrogenic alterations in endothelial cells and cardiac fibroblasts by mediating the NF-κB and Akt pathway.

Heart failure remains a global threaten to public health, cardiac fibrosis being a crucial event during the development and progression of heart failure. Reportedly, M2 macrophages might affect endothelial cell (ECs) and fibroblast proliferation and functions through paracrine signaling, participating in myocardial fibrosis. In this study, differentially expressed paracrine factors between M0/1 and M2 macrophages were analyzed and the expression of TNFSF13 was most significant in M2 macrophages. Culture medium (CM) of M2 (M2 CM) coculture to ECs and cardiac fibroblasts (CFbs) significantly promoted the cell proliferation of ECs and CFbs, respectively, and elevated α-smooth muscle actin (α-SMA), collagen I, and vimentin levels within both cell lines; moreover, M2 CM-induced changes in ECs and CFbs were partially abolished by TNFSF13 knockdown in M2 macrophages. Lastly, the NF-κB and Akt signaling pathways were proved to participate in TNFSF13-mediated M2 CM effects on ECs and CFbs. In conclusion, TNFSF13, a paracrine factor upregulated in M2 macrophages, could mediate the promotive effects of M2 CM on EC and CFb proliferation and fibrogenic alterations.