Background and aims: The enzyme histidine decarboxylase (Hdc), which generates histamine, is highly expressed in CD11b+Gr-1+ myeloid cells that play a critical role in infection, inflammation and tumorigenesis. The aim of this study was to explore the role of Hdc-expressing CD11b+ myeloid cells or histamine in atherogenesis.
Methods: Hdc-EGFP bacterial artificial chromosome (BAC) transgenic reporter mice (Hdc-EGFP) were used to track Hdc expression during the development of atherosclerosis. The expression of EGFP fluorescence was examined by immunofluorescence staining in a variety of adult tissues. Wild-type (WT), Apoe knockout (Apoe-/-), Hdc knockout (Hdc-/-), and Stat6 knockout (Stat6-/-) mice were used. Serum concentration of histamine was determined with ELISA. Changes in subsets of immune cells were evaluated by flow cytometry (FACS). Non-invasive tracking of the expression of CD11b+ myeloid cells was tested using 125I-anti-CD11b SPECT/CT imaging in the early stages of atherogenesis. Microarray analysis and RT-PCR were applied to detect gene expressions while Western blot was used to assess protein levels.
Results: Using Hdc-EGFP transgenic mice, we demonstrated that Hdc+CD11b+ myeloid cells increase in the circulation in response to hypercholesterolemia and contribute to foam cell formation in atherosclerosis. Histamine deficiency in Hdc knockout (Hdc-/-) mice repressed the differentiation of CD11b+Ly6Chigh classically activated M1-type macrophages and CD11b+CD11c+ dendritic cells (DCs), which was associated with downregulation of signal transducer and activator of transcription 6 (Stat6) expression. Furthermore, the results of in vivo and in vitro studies demonstrated that histamine could promote macrophage differentiation and foam cell formation via the Stat6 signal.
Conclusions: Modulation of histamine and Stat6-signaling may represent an attractive therapeutic strategy for the prevention or treatment of atherosclerosis.
Keywords: Foam cell formation; Histamine; Macrophage differentiation; Signal transducer and activator of transcription 6 (Stat6).
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