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EP3 signaling in dendritic cells promotes liver repair by inducing IL‐13‐mediated macrophage differentiation in mice
Author(s) -
Nakamoto Shuji,
Ito Yoshiya,
Nishizawa Nobuyuki,
Goto Takuya,
Kojo Ken,
Kumamoto Yusuke,
Watanabe Masahiko,
Narumiya Shuh,
Majima Masataka
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901955r
Subject(s) - microbiology and biotechnology , macrophage , chemistry , immunology , biology , biochemistry , in vitro
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 low 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 high 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.