组氨酸通过 Stat6 依赖途径促进 CD11b 髓样细胞向巨噬细胞分化和泡沫细胞形成。
Histamine promotes the differentiation of macrophages from CD11b myeloid cells and formation of foam cells through a Stat6-dependent pathway.
机构信息
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
出版信息
Atherosclerosis. 2017 Aug;263:42-52. doi: 10.1016/j.atherosclerosis.2017.05.024. Epub 2017 May 23.
BACKGROUND AND AIMS
The enzyme histidine decarboxylase (Hdc), which generates histamine, is highly expressed in CD11bGr-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-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 HdcCD11b 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 CD11bLy6C classically activated M1-type macrophages and CD11bCD11c 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.
背景与目的
生成组胺的酶组氨酸脱羧酶（Hdc）在 CD11bGr-1 髓样细胞中高度表达，这些细胞在感染、炎症和肿瘤发生中起着关键作用。本研究旨在探讨表达 Hdc 的 CD11b 髓样细胞或组胺在动脉粥样硬化形成中的作用。
方法
使用 Hdc-EGFP 细菌人工染色体（BAC）转基因报告小鼠（Hdc-EGFP）来跟踪动脉粥样硬化发展过程中 Hdc 的表达。通过免疫荧光染色在各种成年组织中检查 EGFP 荧光的表达。使用野生型（WT）、Apoe 基因敲除（Apoe）、Hdc 基因敲除（Hdc）和 Stat6 基因敲除（Stat6）小鼠。使用 ELISA 测定血清组胺浓度。通过流式细胞术（FACS）评估免疫细胞亚群的变化。使用 I-anti-CD11b SPECT/CT 成像在动脉粥样硬化的早期阶段测试 CD11b 髓样细胞表达的非侵入性跟踪。应用微阵列分析和 RT-PCR 检测基因表达，Western blot 检测蛋白水平。
结果
使用 Hdc-EGFP 转基因小鼠，我们证明了 HdcCD11b 髓样细胞在高脂血症时会增加，并有助于动脉粥样硬化中的泡沫细胞形成。Hdc 基因敲除（Hdc）小鼠中的组胺缺乏抑制了 CD11bLy6C 经典激活的 M1 型巨噬细胞和 CD11bCD11c 树突状细胞（DC）的分化，这与信号转导和转录激活因子 6（Stat6）表达下调有关。此外，体内和体外研究的结果表明，组胺可以通过 Stat6 信号促进巨噬细胞分化和泡沫细胞形成。
结论
调节组胺和 Stat6 信号可能代表预防或治疗动脉粥样硬化的一种有吸引力的治疗策略。
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