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

作者：Xu, Lili; Cheng, Dengfeng; Huang, Zheyong; Ding, Suling; Zhang, Weiwei; Tan, Hui; Shi, Hongcheng; Chen, Ruizhen; Zou, Yunzeng; Wang, Timothy C.; Yang, Xiangdong^*; Ge, Junbo^*

来源：Atherosclerosis, 2017, 263: 42-52.

DOI：10.1016/j.atherosclerosis.2017.05.024

• Histamine
• Signal transducer and activator of transcription 6 (Stat6)
• Macrophage differentiation
• Foam cell formation

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 I-125-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.

• 出版日期2017-8
• 单位复旦大学