EP3 signaling in dendritic cells promotes liver repair by inducing IL‐13‐mediated macrophage differentiation in mice. Issue 4 (28th February 2020)

• Record Type: Journal Article
• Authors: Nakamoto, Shuji; Ito, Yoshiya; Nishizawa, Nobuyuki; Goto, Takuya; Kojo, Ken; Kumamoto, Yusuke; Watanabe, Masahiko; Narumiya, Shuh; Majima, Masataka
• Is Part Of: FASEB journal. Volume 34:Issue 4(2020)
• Page Start: 5610
• Page End: 5627
• Publication Date: 2020-02-28
• Subjects: crosstalk -- immune cells -- ischemia -- prostaglandin -- reperfusion; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201901955R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: 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.