Nobuyuki Nishizawa1, Yoshiya Ito2, Koji Eshima3, Hirotoki Ohkubo4, Ken Kojo1, Tomoyoshi Inoue1, Joan Raouf5, Per-Johan Jakobsson5, Satoshi Uematsu6, Shizuo Akira7, Shuh Narumiya8, Masahiko Watanabe9, Masataka Majima10. 1. Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. 2. Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan; Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. 3. Department of Immunology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. 4. Department of Cardiovascular Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. 5. Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Karolinska Institutet, S-171 76 Stockholm, Sweden. 6. Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. 7. Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. 8. Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 9. Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. 10. Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. Electronic address: mmajima@med.kitasto-u.ac.jp.
Abstract
BACKGROUND & AIMS: Liver repair following hepatic ischemia/reperfusion (I/R) injury is crucial to survival. This study aims to examine the role of endogenous prostaglandin E2 (PGE2) produced by inducible microsomal PGE synthase-1 (mPGES-1), a terminal enzyme of PGE2 generation, in liver injury and repair following hepatic I/R. METHODS: mPGES-1 deficient (Ptges-/-) mice or their wild-type (WT) counterparts were subjected to partial hepatic ischemia followed by reperfusion. The role of E prostanoid receptor 4 (EP4) was then studied using a genetic knockout model and a selective antagonist. RESULTS: Compared with WT mice, Ptges-/- mice exhibited reductions in alanine aminotransferase (ALT), necrotic area, neutrophil infiltration, chemokines, and proinflammatory cytokine levels. Ptges-/- mice also showed promoted liver repair and increased Ly6Clow macrophages (Ly6Clow/CD11bhigh/F4/80high-cells) with expression of anti-inflammatory and reparative genes, while WT mice exhibited delayed liver repair and increased Ly6Chigh macrophages (Ly6Chigh/CD11bhigh/F4/80low-cells) with expression of proinflammatory genes. Bone marrow (BM)-derived mPGES-1-deficient macrophages facilitated liver repair with increases in Ly6Clow macrophages. In vitro, mPGES-1 was expressed in macrophages polarized toward the proinflammatory profile. Mice treated with the mPGES-1 inhibitor Compound III displayed increased liver protection and repair. Hepatic I/R enhanced the hepatic expression of PGE receptor subtype, EP4, in WT mice, which was reduced in Ptges-/- mice. A selective EP4 antagonist and genetic deletion of Ptger4, which codes for EP4, accelerated liver repair. The proinflammatory gene expression was upregulated by stimulation of EP4 agonist in WT macrophages but not in EP4-deficient macrophages. CONCLUSIONS: These results indicate that mPGES-1 regulates macrophage polarization as well as liver protection and repair through EP4 signaling during hepatic I/R. Inhibition of mPGES-1 could have therapeutic potential by promoting liver repair after acute liver injury. LAY SUMMARY: Hepatic ischemia/reperfusion injury is a serious complication that occurs in liver surgery. Herein, we demonstrated that inducible prostaglandin E2 synthase (mPGES-1), an enzyme involved in synthesizing prostaglandin E2, worsens the injury and delays liver repair through accumulation of proinflammatory macrophages. Inhibition of mPGES-1 offers a potential therapy for both liver protection and repair in hepatic ischemia/reperfusion injury.
BACKGROUND & AIMS: Liver repair following hepatic ischemia/reperfusion (I/R) injury is crucial to survival. This study aims to examine the role of endogenous prostaglandin E2 (PGE2) produced by inducible microsomal PGE synthase-1 (mPGES-1), a terminal enzyme of PGE2 generation, in liver injury and repair following hepatic I/R. METHODS:mPGES-1 deficient (Ptges-/-) mice or their wild-type (WT) counterparts were subjected to partial hepatic ischemia followed by reperfusion. The role of E prostanoid receptor 4 (EP4) was then studied using a genetic knockout model and a selective antagonist. RESULTS: Compared with WT mice, Ptges-/- mice exhibited reductions in alanine aminotransferase (ALT), necrotic area, neutrophil infiltration, chemokines, and proinflammatory cytokine levels. Ptges-/- mice also showed promoted liver repair and increased Ly6Clow macrophages (Ly6Clow/CD11bhigh/F4/80high-cells) with expression of anti-inflammatory and reparative genes, while WT mice exhibited delayed liver repair and increased Ly6Chigh macrophages (Ly6Chigh/CD11bhigh/F4/80low-cells) with expression of proinflammatory genes. Bone marrow (BM)-derived mPGES-1-deficient macrophages facilitated liver repair with increases in Ly6Clow macrophages. In vitro, mPGES-1 was expressed in macrophages polarized toward the proinflammatory profile. Mice treated with the mPGES-1 inhibitor Compound III displayed increased liver protection and repair. Hepatic I/R enhanced the hepatic expression of PGE receptor subtype, EP4, in WT mice, which was reduced in Ptges-/- mice. A selective EP4 antagonist and genetic deletion of Ptger4, which codes for EP4, accelerated liver repair. The proinflammatory gene expression was upregulated by stimulation of EP4 agonist in WT macrophages but not in EP4-deficient macrophages. CONCLUSIONS: These results indicate that mPGES-1 regulates macrophage polarization as well as liver protection and repair through EP4 signaling during hepatic I/R. Inhibition of mPGES-1 could have therapeutic potential by promoting liver repair after acute liver injury. LAY SUMMARY:Hepatic ischemia/reperfusion injury is a serious complication that occurs in liver surgery. Herein, we demonstrated that inducible prostaglandin E2 synthase (mPGES-1), an enzyme involved in synthesizing prostaglandin E2, worsens the injury and delays liver repair through accumulation of proinflammatory macrophages. Inhibition of mPGES-1 offers a potential therapy for both liver protection and repair in hepatic ischemia/reperfusion injury.
Authors: Madeleine Themanns; Florian Koban; Christian Bergmayr; Alicja Chrzan; Wolfgang Strohmaier; Johannes Haybaeck; Michael Freissmuth; Eva Zebedin-Brandl Journal: J Mol Med (Berl) Date: 2018-12-07 Impact factor: 4.599
Authors: MaryLynn FitzSimons; Megan Beauchemin; Ashley M Smith; Erika G Stroh; Daniel J Kelpsch; Maureen C Lamb; Tina L Tootle; Viravuth P Yin Journal: Sci Rep Date: 2020-02-20 Impact factor: 4.379