Histamine promotes the differentiation of macrophages from CD11b+ myeloid cells and formation of foam cells through a Stat6-dependent pathway

Abstract

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⁺Ly6C^high 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).