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

Atherosclerosis. 2017 Aug;263:42-52. doi: 10.1016/j.atherosclerosis.2017.05.024. Epub 2017 May 23.

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+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).

MeSH terms

  • Animals
  • Atherosclerosis
  • CD11b Antigen / metabolism*
  • Cell Differentiation
  • Dendritic Cells / cytology
  • Female
  • Flow Cytometry
  • Foam Cells / cytology*
  • Green Fluorescent Proteins / metabolism
  • Histamine / metabolism*
  • Macrophages / cytology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Myeloid Cells / cytology*
  • Oligonucleotide Array Sequence Analysis
  • STAT6 Transcription Factor / metabolism*
  • Single Photon Emission Computed Tomography Computed Tomography

Substances

  • CD11b Antigen
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Green Fluorescent Proteins
  • Histamine