Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b + Myeloid Cells in Injured Hearts Post Myocardial Infarction

Myocardial infarction (MI) is a significant contributor to the development of heart failure. Histidine decarboxylase (HDC), the unique enzyme that converts l -histidine to histamine, is highly expressed in CD11b + immature myeloid cells. However, the relationship between HDC-expressing macrophages and cardiac myofibroblasts remains to be explained. Here, we demonstrate that the GFP (green fluorescent protein)-labeled HDC + CD11b + myeloid precursors and their descendants could differentiate into fibroblast-like cells in myocardial interstitium. Furthermore, we prove that CD11b + Ly6C + monocytes/macrophages, but not CD11b + Ly6G + granulocytes, are identified as the main cellular source for bone marrow-derived myofibroblast transformation, which could be regulated via histamine H1 and H2 receptor-dependent signaling pathways. Using HDC knockout mice, we find that histamine deficiency promotes myofibroblast transformation from Ly6C + macrophages and cardiac fibrosis partly through upregulating the expression of Krüppel-like factor 5 (KLF5). Taken together, our data uncover a central role of HDC in regulating bone marrow-derived macrophage-to-myofibroblast transformation but also identify a histamine receptor (HR)-KLF5 related signaling pathway that mediates myocardial fibrosis post-MI. Graphical abstract CD11b + Ly6C + monocytes/macrophages are the main cellular source for bone marrow-derived myofibroblast transformation. Histamine inhibits myofibroblasts transformation via H1R and H2R-dependent signaling pathways, and ameliorates cardiac fibrosis partly through upregulating KLF5 expression.