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. [Figure not available: see fulltext.]