EP3 signaling in dendritic cells promotes liver repair by inducing IL‐13‐mediated macrophage differentiation in mice

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  • Shuji Nakamoto
    Department of Molecular Pharmacology Graduate School of Medical Sciences Kitasato University Sagamihara Japan
  • Yoshiya Ito
    Department of Molecular Pharmacology Graduate School of Medical Sciences Kitasato University Sagamihara Japan
  • Nobuyuki Nishizawa
    Department of Pharmacology Kitasato University School of Medicine Sagamihara Japan
  • Takuya Goto
    Department of Molecular Pharmacology Graduate School of Medical Sciences Kitasato University Sagamihara Japan
  • Ken Kojo
    Department of Surgery Kitasato University School of Medicine Sagamihara Japan
  • Yusuke Kumamoto
    Department of Surgery Kitasato University School of Medicine Sagamihara Japan
  • Masahiko Watanabe
    Department of Surgery Kitasato University School of Medicine Sagamihara Japan
  • Shuh Narumiya
    Center for Innovation in Immunoregulation Technology and Therapeutics Kyoto University Graduate School of Medicine Kyoto Japan
  • Masataka Majima
    Department of Molecular Pharmacology Graduate School of Medical Sciences Kitasato University Sagamihara Japan

書誌事項

公開日
2020-02-28
資源種別
journal article
権利情報
  • http://onlinelibrary.wiley.com/termsAndConditions#vor
DOI
  • 10.1096/fj.201901955r
公開者
Wiley

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<jats:title>Abstract</jats:title> <jats:p> 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 <jats:sup>−/−</jats:sup> ) 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, <jats:italic>Ptger3</jats:italic> <jats:sup>−/−</jats:sup> mice showed delayed liver repair accompanied by reduced expression of hepatic growth factors and accumulation of Ly6C <jats:sup>low</jats:sup> 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 <jats:italic>Ptger3</jats:italic> <jats:sup>−/−</jats:sup> mice resulted in impaired repair, along with increased numbers of Ly6C <jats:sup>high</jats:sup> 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. </jats:p>

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