Herová Magdalena, Schmid Mattia, Gemperle Claudio, Hersberger Martin
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland.
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland
J Immunol. 2015 Mar 1;194(5):2330-7. doi: 10.4049/jimmunol.1402166. Epub 2015 Jan 30.
ChemR23 is a G protein-coupled receptor that is triggered by two ligands, the peptide chemerin and the eicosapentaenoic acid-derived lipid mediator resolvin E1 (RvE1). Chemerin acts as a chemoattractant for monocytes and macrophages, whereas RvE1 promotes resolution of inflammation-inducing macrophage phagocytosis of apoptotic neutrophils. Although ChemR23-mediated signaling plays a role in mononuclear cell migration to inflamed tissue, as well as in the resolution of inflammation, its regulation in different polarization states of macrophages is largely unknown. We analyzed the expression and function of ChemR23 in monocytes and differently activated human primary macrophages. Using 5' RACE, we identified three transcription start sites and several splice variants of ChemR23 in both monocytes and macrophages. Although the promoters P1 and P3 are used equally in unpolarized macrophages, stimulation with LPS or IFN-γ leads to increased transcription from P3 in inflammatory M1 macrophages. Such ChemR23-expressing M1 macrophages are chemotactic to chemerin, whereas M2 macrophages not expressing ChemR23 surface receptor are not. Repolarization of ChemR23-expressing M1 macrophages with 10 nM RvE1 increases IL-10 transcription and phagocytosis of microbial particles, leading to a resolution-type macrophage distinct from the M2 phenotype. These results show that ChemR23 is tightly regulated in response to inflammatory and anti-inflammatory stimuli. The restricted expression of ChemR23 in naive and M1 macrophages supports the role of ChemR23 in the attraction of macrophages to inflamed tissue by chemerin and in the initiation of resolution of inflammation through RvE1-mediated repolarization of human M1 macrophages toward resolution-type macrophages.
ChemR23是一种G蛋白偶联受体，可被两种配体激活，即肽类chemerin和二十碳五烯酸衍生的脂质介质消退素E1（RvE1）。chemerin作为单核细胞和巨噬细胞的趋化因子，而RvE1则促进炎症消退，诱导巨噬细胞吞噬凋亡的中性粒细胞。尽管ChemR23介导的信号传导在单核细胞向炎症组织的迁移以及炎症消退中发挥作用，但其在巨噬细胞不同极化状态下的调节机制仍 largely未知。我们分析了ChemR23在单核细胞和不同激活状态的人原代巨噬细胞中的表达和功能。通过5'RACE，我们在单核细胞和巨噬细胞中鉴定出了ChemR23的三个转录起始位点和多个剪接变体。尽管在未极化的巨噬细胞中，启动子P1和P3的使用频率相同，但用LPS或IFN-γ刺激会导致炎症性M1巨噬细胞中P3的转录增加。这种表达ChemR23的M1巨噬细胞对chemerin具有趋化性，而不表达ChemR23表面受体的M2巨噬细胞则没有。用10 nM RvE1对表达ChemR23的M1巨噬细胞进行再极化，可增加IL-10的转录和微生物颗粒的吞噬作用，从而产生一种不同于M2表型的消退型巨噬细胞。这些结果表明，ChemR23在炎症和抗炎刺激下受到严格调控。ChemR23在幼稚巨噬细胞和M1巨噬细胞中的限制性表达支持了ChemR23在chemerin吸引巨噬细胞至炎症组织以及通过RvE1介导的人M1巨噬细胞向消退型巨噬细胞再极化启动炎症消退中的作用。
