Faculty of Dental Medicine, Institute for Dental Sciences, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Biology, The Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
Front Immunol. 2018 Mar 1;9:358. doi: 10.3389/fimmu.2018.00358. eCollection 2018.
The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells (PMN) by local macrophages (efferocytosis) and the consequent reprogramming of the engulfing phagocytes to reparative and pro-resolving phenotypes. The tyrosine kinase receptors TYRO3, AXL, and MERTK (collectively named TAM) are fundamental mediators in regulating inflammatory responses and efferocytosis. Protein S (PROS1) is a ligand for all TAM receptors that mediates various aspects of their activity. However, the involvement of PROS1 in the resolution of inflammation is incompletely understood. Here, we report the upregulation of in macrophages during the resolution of inflammation. Selective knockout of in the myeloid lineage significantly downregulated macrophage pro-resolving properties. Hence, -deficient macrophages engulfed fewer apoptotic PMN remnants , and exogenous PROS1 rescued impaired efferocytosis . Moreover, -deficient peritoneal macrophages secreted higher levels of the pro-inflammatory mediators TNFα and CCL3, while they secreted lower levels of the reparative/anti-inflammatory IL-10 following exposure to lipopolysaccharide in comparison to their WT counterparts. Moreover, -deficient macrophages expressed less of the anti-inflammatory/pro-resolving enzymes arginase-1 and 12/15-lipoxygenase and produced less of the specialized pro-resolving mediator resolvin D1. Altogether, our results suggest that macrophage-derived PROS1 is an important effector molecule in regulating the efferocytosis, maturation, and reprogramming of resolution phase macrophages, and imply that PROS1 could provide a new therapeutic target for inflammatory and fibrotic disorders.
炎症的完全消退需要局部巨噬细胞（吞噬作用）摄取凋亡的多形核细胞（PMN），并随后将吞噬细胞重编程为修复和促解决的表型。酪氨酸激酶受体 TYRO3、AXL 和 MERTK（统称为 TAM）是调节炎症反应和吞噬作用的基本介质。蛋白 S（PROS1）是所有 TAM 受体的配体，介导它们活性的各个方面。然而，PROS1 参与炎症消退的程度尚不完全清楚。在这里，我们报告在炎症消退过程中巨噬细胞中 上调。髓系谱系中 的选择性敲除显着下调了巨噬细胞的促解决特性。因此，-缺陷巨噬细胞吞噬的凋亡 PMN 残余物 减少，外源性 PROS1 挽救了吞噬作用受损 。此外，与 WT 相比，-缺陷的腹腔巨噬细胞在暴露于脂多糖后分泌更高水平的促炎介质 TNFα和 CCL3，而分泌的修复/抗炎 IL-10 水平较低。此外，-缺陷的巨噬细胞表达的抗炎/促解决酶精氨酸酶-1 和 12/15-脂氧合酶较少，产生的特殊促解决介质 resolvin D1 较少。总之，我们的结果表明，巨噬细胞衍生的 PROS1 是调节吞噬作用、成熟和解决阶段巨噬细胞重编程的重要效应分子，并暗示 PROS1 可能为炎症和纤维化疾病提供新的治疗靶点。
