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Paraoxonase 1 (PON1) reduces macrophage inflammatory responses

  • Saar Aharoni
    Affiliations
    The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel
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  • Michael Aviram
    Affiliations
    The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel
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  • Bianca Fuhrman
    Correspondence
    Corresponding author. Tel.: +972 4 8295278; fax: +972 4 8520076.
    Affiliations
    The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel
    Search for articles by this author

      Highlights

      • Paraoxonase 1 (PON1) directly suppresses macrophage pro-inflammatory responses in vitro and in vivo.
      • Functionally, PON1 attenuates M1-induced ROS (radical oxygen species) production, phagocytosis, and necrotic macrophage death.
      • PON1 contributes to the anti-inflammatory effect of high-density lipoprotein (HDL).
      • PON1 anti-inflammatory activity is mediated via interaction with the scavenger receptor class BI (SR-BI) independently of cholesterol efflux.

      Abstract

      Objectives

      Paraoxonase 1 (PON1) was suggested to play an anti-inflammatory role. In the present study we questioned whether PON1 has a direct impact on macrophage inflammatory responses, and the possible functional implications of such effects.

      Methods and results

      Ex-vivo studies were performed with bone marrow-derived macrophages (BMDM) harvested from C57BL/6 and human-PON1 transgenic (PON1-Tg) mice, and for the in vitro studies the J774.A1 macrophage-like cell line was used. Pro-inflammatory (M1) activation was induced by LPS and INFγ. The spontaneous and M1-induced TNFα and IL-6 secretion were significantly reduced in BMDM derived from PON1-Tg vs. C57BL/6 mice. In vitro, PON1 dose-dependently attenuated both the spontaneous and M1-induced TNFα and IL-6 secretion, and contributed to the anti-inflammatory activity of HDL. Functionally, PON1 attenuated M1-induced production of reactive oxygen species (ROS), phagocytosis, and necrotic macrophage death. PON1 anti-inflammatory activity was mediated, at least in part, via binding to SR-BI, but was independent of the enzyme catalytic activity or of cholesterol efflux stimulation, and did not involve binding to ABCA1.

      Conclusions

      The present study demonstrates, for the first time, that PON1 directly suppresses macrophage pro-inflammatory responses. These findings suggest that PON1 decreases sustained pro-inflammatory reactions, which subsequently can attenuate plaque progression.

      Keywords

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      References

        • Ross R.
        Atherosclerosis – an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Mosser D.M.
        • Edwards J.P.
        Exploring the full spectrum of macrophage activation.
        Nat Rev Immunol. 2008; 8: 958-969
        • Martinez F.O.
        • Sica A.
        • Mantovani A.
        • Locati M.
        Macrophage activation and polarization.
        Front Biosci. 2008; 13: 453-461
        • Bouhlel M.A.
        • Derudas B.
        • Rigamonti E.
        • et al.
        PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.
        Cell Metab. 2007; 6: 137-143
        • Mantovani A.
        • Garlanda C.
        • Locati M.
        Macrophage diversity and polarization in atherosclerosis: a question of balance.
        Arterioscler Thromb Vasc Biol. 2009; 29: 1419-1423
        • Deakin S.
        • Leviev I.
        • Gomaraschi M.
        • Calabresi L.
        • Franceschini G.
        • James R.W.
        Enzymatically active paraoxonase-1 is located at the external membrane of producing cells and released by a high affinity, saturable, desorption mechanism.
        J Biol Chem. 2002; 277: 4301-4308
        • Tward A.
        • Xia Y.R.
        • Wang X.P.
        • et al.
        Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice.
        Circulation. 2002; 106: 484-490
        • Aviram M.
        • Kaplan M.
        • Rosenblat M.
        • Fuhrman B.
        Dietary antioxidants and paraoxonases against LDL oxidation and atherosclerosis development.
        Handb Exp Pharmacol. 2005; 170: 263-300
        • Aviram M.
        • Rosenblat M.
        • Bisgaier C.L.
        • Newton R.S.
        • Primo-Parmo S.L.
        • La Du B.N.
        Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase.
        J Clin Invest. 1998; 101: 1581-1590
        • Rozenberg O.
        • Shih D.M.
        • Aviram M.
        Paraoxonase 1 (PON1) attenuates macrophage oxidative status: studies in PON1 transfected cells and in PON1 transgenic mice.
        Atherosclerosis. 2005; 181: 9-18
        • Berrougui H.
        • Loued S.
        • Khalil A.
        Purified human paraoxonase-1 interacts with plasma membrane lipid rafts and mediates cholesterol efflux from macrophages.
        Free Radic Biol Med. 2012; 52: 1372-1381
        • Tavori H.
        • Vaya J.
        • Aviram M.
        Paraoxonase 1 attenuates human plaque atherogenicity: relevance to the enzyme lactonase activity.
        Adv Exp Med Biol. 2010; 660: 99-111
        • Watson A.D.
        • Berliner J.A.
        • Hama S.Y.
        • et al.
        Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein.
        J Clin Invest. 1995; 96: 2882-2891
        • Ahmed Z.
        • Babaei S.
        • Maguire G.F.
        • et al.
        Paraoxonase-1 reduces monocyte chemotaxis and adhesion to endothelial cells due to oxidation of palmitoyl, linoleoyl glycerophosphorylcholine.
        Cardiovasc Res. 2003; 57: 225-231
        • Rosenblat M.
        • Volkova N.
        • Ward J.
        • Aviram M.
        Paraoxonase 1 (PON1) inhibits monocyte-to-macrophage differentiation.
        Atherosclerosis. 2011; 219: 49-56
        • Ng D.S.
        • Chu T.
        • Esposito B.
        • Hui P.
        • Connelly P.W.
        • Gross P.L.
        Paraoxonase-1 deficiency in mice predisposes to vascular inflammation, oxidative stress, and thrombogenicity in the absence of hyperlipidemia.
        Cardiovasc Pathol. 2008; 17: 226-232
        • Efrat M.
        • Aviram M.
        Macrophage paraoxonase 1 (PON1) binding sites.
        Biochem Biophys Res Commun. 2008; 376: 105-110
        • Khersonsky O.
        • Tawfik D.S.
        The histidine 115-histidine 134 dyad mediates the lactonase activity of mammalian serum paraoxonases.
        J Biol Chem. 2006; 281: 7649-7656
        • Deakin S.P.
        • Bioletto S.
        • Bochaton-Piallat M.L.
        • James R.W.
        HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress.
        Free Radic Biol Med. 2011; 50: 102-109
        • Chen Y.J.
        • Hsieh M.Y.
        • Chang M.Y.
        • et al.
        Eps8 protein facilitates phagocytosis by increasing TLR4-MyD88 protein interaction in lipopolysaccharide-stimulated macrophages.
        J Biol Chem. 2012; 287: 18806-18819
        • Nieland T.J.
        • Shaw J.T.
        • Jaipuri F.A.
        • et al.
        Identification of the molecular target of small molecule inhibitors of HDL receptor SR-BI activity.
        Biochemistry. 2008; 47: 460-472
        • Fuhrman B.
        • Gantman A.
        • Aviram M.
        Paraoxonase 1 (PON1) deficiency in mice is associated with reduced expression of macrophage SR-BI and consequently the loss of HDL cytoprotection against apoptosis.
        Atherosclerosis. 2010; 211: 61-68
        • Cai L.
        • Wang Z.
        • Ji A.
        • Meyer J.M.
        • van der Westhuyzen D.R.
        Macrophage SR-BI regulates pro-inflammatory signaling in mice and isolated macrophages.
        J Lipid Res. 2012; 53: 1472-1481
        • Zhu P.
        • Liu X.
        • Treml L.S.
        • Cancro M.P.
        • Freedman B.D.
        Mechanism and regulatory function of CpG signaling via scavenger receptor B1 in primary B cells.
        J Biol Chem. 2009; 284: 22878-22887
        • Saddar S.
        • Mineo C.
        • Shaul P.W.
        Signaling by the high-affinity HDL receptor scavenger receptor B type I.
        Arterioscler Thromb Vasc Biol. 2010; 30: 144-150
        • Guo L.
        • Song Z.
        • Li M.
        • et al.
        Scavenger receptor BI protects against septic death through its role in modulating inflammatory response.
        J Biol Chem. 2009; 284: 19826-19834
        • Seimon T.
        • Tabas I.
        Mechanisms and consequences of macrophage apoptosis in atherosclerosis.
        J Lipid Res. 2009; 50: S382-S387
        • Yan Z.Q.
        • Hansson G.K.
        Innate immunity, macrophage activation, and atherosclerosis.
        Immunol Rev. 2007; 219: 187-203
        • Baitsch D.
        • Bock H.H.
        • Engel T.
        • et al.
        Apolipoprotein E induces antiinflammatory phenotype in macrophages.
        Arterioscler Thromb Vasc Biol. 2011; 31: 1160-1168
        • Chinetti-Gbaguidi G.
        • Baron M.
        • Bouhlel M.A.
        • et al.
        Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways.
        Circ Res. 2011; 108: 985-995
        • Mosser D.M.
        The many faces of macrophage activation.
        J Leukoc Biol. 2003; 73: 209-212
        • Gordon S.
        Macrophage heterogeneity and tissue lipids.
        J Clin Invest. 2007; 117: 89-93