J Clin Invest. 2019 Dec 2;129(12):5294-5311. doi: 10.1172/JCI129448.
Resolution of acute inflammation is an active process orchestrated by endogenous mediators and mechanisms pivotal in host defense and homeostasis. The macrophage mediator in resolving inflammation, maresin 1 (MaR1), is a potent immunoresolvent, stimulating resolution of acute inflammation and organ protection. Using an unbiased screening of greater than 200 GPCRs, we identified MaR1 as a stereoselective activator for human leucine-rich repeat containing G protein-coupled receptor 6 (LGR6), expressed in phagocytes. MaR1 specificity for recombinant human LGR6 activation was established using reporter cells expressing LGR6 and functional impedance sensing. MaR1-specific binding to LGR6 was confirmed using 3H-labeled MaR1. With human and mouse phagocytes, MaR1 (0.01-10 nM) enhanced phagocytosis, efferocytosis, and phosphorylation of a panel of proteins including the ERK and cAMP response element-binding protein. These MaR1 actions were significantly amplified with LGR6 overexpression and diminished by gene silencing in phagocytes. Thus, we provide evidence for MaR1 as an endogenous activator of human LGR6 and a novel role of LGR6 in stimulating MaR1's key proresolving functions of phagocytes.
急性炎症的消退是一个由内源性介质和机制协调的主动过程，这些介质和机制对宿主防御和内稳态至关重要。在消退炎症的巨噬细胞介质中，maresin 1（MaR1）是一种有效的免疫溶剂，可刺激急性炎症消退和器官保护。我们使用超过 200 种 G 蛋白偶联受体（GPCR）的无偏筛选方法，鉴定出 MaR1 是人类富含亮氨酸重复序列的 G 蛋白偶联受体 6（LGR6）的立体选择性激活剂，该受体在吞噬细胞中表达。MaR1 对重组人 LGR6 激活的特异性是使用表达 LGR6 和功能性阻抗感应的报告细胞来建立的。使用 3H 标记的 MaR1 证实了 MaR1 对 LGR6 的特异性结合。用人类和小鼠吞噬细胞，MaR1（0.01-10 nM）增强了吞噬作用、吞噬作用和一系列蛋白的磷酸化，包括 ERK 和 cAMP 反应元件结合蛋白。在吞噬细胞中过表达 LGR6 可显著放大这些 MaR1 作用，而基因沉默则减弱了这些作用。因此，我们提供了证据表明 MaR1 是人类 LGR6 的内源性激活剂，并且 LGR6 在刺激 MaR1 的吞噬细胞关键抗炎功能方面具有新的作用。
