Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan.
FASEB J. 2020 Apr;34(4):5610-5627. doi: 10.1096/fj.201901955R. Epub 2020 Feb 28.
Macrophage plasticity is essential for liver wound healing; however, the mechanisms underlying macrophage phenotype switching are largely unknown. Dendritic cells (DCs) are critical initiators of innate immune responses; as such, they orchestrate inflammation following hepatic injury. Here, we subjected EP3-deficient (Ptger3 ) and wild-type (WT) mice to hepatic ischemia-reperfusion (I/R) and demonstrate that signaling via the prostaglandin E (PGE) receptor EP3 in DCs regulates macrophage plasticity during liver repair. Compared with WT mice, Ptger3 mice showed delayed liver repair accompanied by reduced expression of hepatic growth factors and accumulation of Ly6C reparative macrophages and monocyte-derived DCs (moDCs). MoDCs were recruited to the boundary between damaged and undamaged liver tissue in an EP3-dependent manner. Adoptive transfer of moDCs from Ptger3 mice resulted in impaired repair, along with increased numbers of Ly6C inflammatory macrophages. Bone marrow macrophages (BMMs) up-regulated expression of genes related to a reparative macrophage phenotype when co-cultured with moDCs; this phenomenon was dependent on EP3 signaling. In the presence of an EP3 agonist, interleukin (IL)-13 derived from moDCs drove BMMs to increase expression of genes characteristic of a reparative macrophage phenotype. The results suggest that EP3 signaling in moDCs facilitates liver repair by inducing IL-13-mediated switching of macrophage phenotype from pro-inflammatory to pro-reparative.
巨噬细胞可塑性对于肝脏伤口愈合至关重要；然而，巨噬细胞表型转换的机制在很大程度上尚不清楚。树突状细胞（DCs）是先天免疫反应的关键启动者；因此，它们在肝损伤后协调炎症反应。在这里，我们对 EP3 缺陷型（Ptger3 ）和野生型（WT）小鼠进行了肝缺血再灌注（I/R）处理，并证明 DC 中前列腺素 E（PGE）受体 EP3 的信号转导调节了肝修复过程中的巨噬细胞可塑性。与 WT 小鼠相比，Ptger3 小鼠表现出延迟的肝脏修复，伴随着肝生长因子表达减少和 Ly6C 修复性巨噬细胞和单核细胞衍生的 DC（moDC）积累。MoDC 以 EP3 依赖的方式募集到受损和未受损肝组织之间的边界。从 Ptger3 小鼠中过继转移 moDC 会导致修复受损，同时炎症性 Ly6C 巨噬细胞数量增加。骨髓来源的巨噬细胞（BMMs）与 moDC 共培养时上调与修复性巨噬细胞表型相关的基因表达；这种现象依赖于 EP3 信号。在 EP3 激动剂存在的情况下，moDC 衍生的白细胞介素（IL）-13 促使 BMMs增加表达具有修复性巨噬细胞表型特征的基因。结果表明，moDC 中的 EP3 信号通过诱导 IL-13 介导的巨噬细胞表型从促炎向修复性转换，促进肝脏修复。
