Advertisement

Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice

Published:February 17, 2018DOI:https://doi.org/10.1016/j.jhep.2018.02.009

      Highlights

      • mPGES-1/PGE2/EP4 pathway is enhanced during hepatic I/R.
      • Recruitment of mPGES-1+Ly6Chigh -macrophages delays liver repair.
      • EP4 signaling directs macrophages into a pro-inflammatory phenotype.
      • mPGES-1 inhibitor attenuates liver injury and promotes liver repair.

      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.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Selzner N.
        • Rudiger H.
        • Graf R.
        • et al.
        Protective strategies against ischemic injury of the liver.
        Gastroenterology. 2003; 125: 917-936
        • de Rougemont O.
        • Dutkowski P.
        • Clavien P.A.
        Biological modulation of liver ischemia-reperfusion injury.
        Curr Opin Organ Transplant. 2010; 15: 183-189
        • Lentsch A.B.
        Regulatory mechanisms of injury and repair after hepatic ischemia/reperfusion.
        Scientifica. 2012; 2012: 513192
        • Katori M.
        • Majima M.
        Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors.
        Inflamm Res. 2000; 49: 367-392
        • Samuelsson B.
        • Morgenstern R.
        • Jakobsson P.J.
        Membrane prostaglandin E synthase-1: a novel therapeutic target.
        Pharmacol Rev. 2007; 59: 207-224
        • Boulet L.
        • Ouellet M.
        • Bateman K.P.
        • et al.
        Deletion of microsomal prostaglandin E2 (PGE2) synthase-1 reduces inducible and basal PGE2 production and alters the gastric prostanoid profile.
        J Biol Chem. 2004; 279: 23229-23237
        • Ikeda-Matsuo Y.
        • Ota A.
        • Fukada T.
        • et al.
        Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury.
        Proc Natl Acad Sci U S A. 2006; 103: 11790-11795
        • Hamada T.
        • Tsuchihashi S.
        • Avanesyan A.
        • et al.
        Cyclooxygenase-2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury.
        J Immunol. 2008; 180: 1843-1853
        • Hossain M.A.
        • Hamamoto I.
        • Wakabayashi H.
        • et al.
        Experimental study of the effect of intraportal prostaglandin E1 on hepatic blood flow during reperfusion after ischaemia and hepatectomy.
        Br J Surg. 1999; 86: 776-783
        • Kuzumoto Y.
        • Sho M.
        • Ikeda N.
        • et al.
        Significance and therapeutic potential of prostaglandin E-2 receptor in hepatic ischemia/reperfusion injury in mice.
        Hepatology. 2005; 42: 608-617
        • Paralkar V.M.
        • Borovecki F.
        • Ke H.Z.
        • et al.
        An EP2 receptor-selective prostaglandin E2 agonist induces bone healing.
        Proc Natl Acad Sci U S A. 2003; 100: 6736-6740
        • Kim H.B.
        • Kim M.
        • Park Y.S.
        • et al.
        Prostaglandin E2 activates YAP and a positive-signaling loop to promote colon regeneration following colitis but also carcinogenesis in mice.
        Gastroenterology. 2017; 152: 616-630
        • Refsnes M.
        • Dajani O.F.
        • Sandnes D.
        • et al.
        On the mechanisms of the growth-promoting effect of prostaglandins in hepatocytes: the relationship between stimulation of DNA synthesis and signaling mediated by adenylyl cyclase and phosphoinositide-specific phospholipase C.
        J Cell Physiol. 1995; 164: 465-473
        • Zhang Y.
        • Desai A.
        • Yang S.Y.
        • et al.
        TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.
        Science. 2015; 348: aaa2340
        • Uematsu S.
        • Matsumoto M.
        • Takeda K.
        • et al.
        Lipopolysaccharide-dependent prostaglandin E2 production is regulated by the glutathione-dependent prostaglandin E2 synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway.
        J Immunol. 2002; 168: 5811-5816
        • Segi E.
        • Sugimoto Y.
        • Yamasaki A.
        • et al.
        Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice.
        Biochem Biophys Res Commun. 1998; 246: 7-12
        • Ohkubo H.
        • Ito Y.
        • Minamino T.
        • et al.
        Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment.
        FASEB J. 2013; 27: 3132-3143
        • De Simone R.
        • Chini M.G.
        • Bruno I.
        • et al.
        Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents.
        J Med Chem. 2011; 54: 1565-1575
        • Jaeschke H.
        Mechanisms of liver injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1083-G1088
        • Sugimoto Y.
        • Narumiya S.
        Prostaglandin E receptors.
        J Biol Chem. 2007; 282: 11613-11617
        • Kato T.
        • Ito Y.
        • Kanako H.
        • et al.
        Vascular endothelial growth factor receptor-1 signaling promotes liver repair through restoration of liver microvasculature after acetaminophen hepatotoxicity.
        Toxicol Sci. 2011; 120: 218-229
        • Ohkubo H.
        • Ito Y.
        • Minamino T.
        • et al.
        VEGFR1-positive macrophages facilitate liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion injury.
        PLoS One. 2014; 9: e105533
        • Tacke F.
        • Zimmermann H.W.
        Macrophage heterogeneity in liver injury and fibrosis.
        J Hepatol. 2014; 60: 1090-1096
        • Ju C.
        • Tacke F.
        Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies.
        Cell Mol Immunol. 2016; 13: 316-327
        • Zigmond E.
        • Samia-Grinberg S.
        • Pasmanik-Chor M.
        • et al.
        Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury.
        J Immunol. 2014; 193: 344-353
        • Dal-Secco D.
        • Wang J.
        • Zeng Z.
        • et al.
        A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury.
        J Exp Med. 2015; 212: 447-456
        • McDonald B.
        • Kubes P.
        Innate immune cell trafficking and function during sterile inflammation of the liver.
        Gastroenterology. 2016; 151: 1087-1095
        • Mossanen J.C.
        • Krenkel O.
        • Ergen C.
        • et al.
        Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury.
        Hepatology. 2016; 64: 1667-1682
        • Zasłona Z.
        • Pålsson-McDermott E.M.
        • Menon D.
        • et al.
        The induction of pro-IL-1β by lipopolysaccharide requires endogenous prostaglandin E(2) production.
        J Immunol. 2017; 198: 3558-3564
        • Degousee N.
        • Fazel S.
        • Angoulvant D.
        • et al.
        Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction.
        Circulation. 2008; 117: 1701-1710
        • Yu J.
        • Gong W.
        • Wu Y.
        • et al.
        MPGES-1-derived PGE2 contributes to adriamycin-induced podocyte injury.
        Am J Physiol Renal Physiol. 2016; 310: F492-F498
        • Coulombe F.
        • Jaworska J.
        • Verway M.
        • et al.
        Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages.
        Immunity. 2014; 40: 554-568
        • Yao C.
        • Sakata D.
        • Esaki Y.
        • et al.
        Prostaglandin E2-EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion.
        Nat Med. 2009; 15: 633-640
        • Chen Q.
        • Muramoto K.
        • Masaaki N.
        • et al.
        A novel antagonist of the prostaglandin E2 EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.
        Br J Pharmacol. 2010; 160: 292-310
        • Hishikari K.
        • Suzuki J.
        • Ogawa M.
        • et al.
        Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury.
        Cardiovasc Res. 2009; 81: 123-132