Oxidized Phospholipids as Endogenous Pattern Recognition Ligands in Innate Immunity

One of the major functions of the innate immune system is the surveillance of host tissues, identifying apoptotic and senescent cells for engulfment and orderly removal by macrophages (1Ravichandran K.S. Lorenz U. Nat. Rev. Immunol. 2007; 7: 964-974Crossref PubMed Scopus (512) Google Scholar, 2Stuart L.M. Ezekowitz R.A. Immunity. 2005; 22: 539-550Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar). Macrophage recognition of modified lipoproteins occurs via similar pathways of the innate immune system, involving shared scavenger receptors and molecular pattern recognition ligands (3Shaw P.X. Hörkkö S. Chang M.K. Curtiss L.K. Palinski W. Silverman G.J. Witztum J.L. J. Clin. Investig. 2000; 105: 1731-1740Crossref PubMed Scopus (557) Google Scholar, 4Hazen S.L. Chisolm G.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 12515-12517Crossref PubMed Scopus (32) Google Scholar, 5Chang M.K. Bergmark C. Laurila A. Hörkkö S. Han K.H. Friedman P. Dennis E.A. Witztum J.L. Proc. Natl. 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Science. 1989; 243: 1469-1471Crossref PubMed Scopus (258) Google Scholar, 16Oquendo P. Hundt E. Lawler J. Seed B. Cell. 1989; 8: 95-101Abstract Full Text PDF Scopus (400) Google Scholar). It also recognizes oxidatively modified lipoproteins, leading to cholesterol accumulation and atherosclerotic plaque development in vivo (17Endemann G. Stanton L.W. Madden K.S. Bryant C.M. White R.T. Protter A.A. J. Biol. Chem. 1993; 268: 11811-11816Abstract Full Text PDF PubMed Google Scholar, 18Febbraio M. Podrez E.A. Smith J.D. Hajjar D.P. Hazen S.L. Hoff H.F. Sharma K. Silverstein R.L. J. Clin. Investig. 2000; 105: 1049-1056Crossref PubMed Scopus (825) Google Scholar). Recent data support the notion that phospholipid oxidation within cell membranes and lipoproteins exposes similar molecular patterns recognized by CD36 and other receptors of innate immunity. Animal model studies with mice genetically engineered to lack functional CD36 confirm that this prototypic scavenger receptor participates in recognition and engulfment of apoptotic cells (19Greenberg M.E. Sun M. Zhang R. Febbraio M. Silverstein R. Hazen S.L. J. Exp. Med. 2006; 203: 2613-2625Crossref PubMed Scopus (319) Google Scholar), senescent cells or cell fragments (20Sun M. Finnemann S.C. Febbraio M. Shan L. Annangudi S.P. Podrez E.A. Hoppe G. Darrow R. Organisciak D.T. Salomon R.G. Silverstein R.L. Hazen S.L. J. Biol. Chem. 2006; 281: 4222-4230Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), and oxLDL 2The abbreviations used are: oxLDL, oxidized low density lipoprotein; oxPC, oxidized phosphatidylcholine; oxPL, oxidized phospholipid(s); oxPCCD36, oxidized PC species possessing an sn-2 acyl group that incorporates a terminal γ-hydroxy(or oxo)-α,β-unsaturated carbonyl; oxPS, oxidized phosphatidylserine; MS, mass spectrometric/spectrometry; PLA2, phospholipase A2. 2The abbreviations used are: oxLDL, oxidized low density lipoprotein; oxPC, oxidized phosphatidylcholine; oxPL, oxidized phospholipid(s); oxPCCD36, oxidized PC species possessing an sn-2 acyl group that incorporates a terminal γ-hydroxy(or oxo)-α,β-unsaturated carbonyl; oxPS, oxidized phosphatidylserine; MS, mass spectrometric/spectrometry; PLA2, phospholipase A2. in vivo (18Febbraio M. Podrez E.A. Smith J.D. Hajjar D.P. Hazen S.L. Hoff H.F. Sharma K. Silverstein R.L. J. Clin. Investig. 2000; 105: 1049-1056Crossref PubMed Scopus (825) Google Scholar, 21Rahaman S.O. Lennon D.J. Febbraio M. Podrez E.A. Hazen S.L. Silverstein R.L. Cell Metab. 2006; 4: 211-221Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). This review will discuss recent discoveries regarding the structural nature of oxidized phospholipids that serve as high affinity ligands for CD36 in vivo. Also discussed will be the Lipid Whisker Model (22Greenberg M.E. Li X.M. Gugiu B.G. Gu X. Qin J. Salomon R.G. Hazen S.L. J. Biol. Chem. 2008; 283: 2385-2396Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). A revision to the Fluid Mosaic Model (23Singer S.J. Nicolson G.L. Science. 1972; 175: 720-731Crossref PubMed Scopus (6091) Google Scholar), the Lipid Whisker Model focuses on phospholipid conformation within oxidized cell membranes and lipoproteins and is derived from recent studies demonstrating the generality of a conformational switch in the structure of many phospholipids within cell membranes that occurs following oxidation. The conformational switch, involving the protrusion of oxidized fatty acids from the hydrophobic membrane interior into the more polar aqueous compartment (22Greenberg M.E. Li X.M. Gugiu B.G. Gu X. Qin J. Salomon R.G. Hazen S.L. J. Biol. Chem. 2008; 283: 2385-2396Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 24Li X.M. Salomon R.G. Qin J. Hazen S.L. Biochemistry. 2007; 46: 5009-5017Crossref PubMed Scopus (39) Google Scholar), facilitates physical contact between pattern recognition receptor and molecular pattern ligand. This anatomic positioning of oxidized fatty acids of membrane phospholipids may also underlie the preferential selectivity of some phospholipases for oxidized fatty acids during membrane remodeling. Recognition of oxidatively modified lipids on the surface of cell membranes and lipoprotein particles plays an important role in numerous innate immune functions and can trigger diverse cellular processes (25Gordon S. Cell. 2002; 111: 927-930Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar, 26Li A.C. Glass C.K. Nat. Med. 2002; 8: 1235-1242Crossref PubMed Scopus (603) Google Scholar, 27Kagan V.E. Tyurin V.A. Jiang J. Tyurina Y.Y. Ritov V.B. Amoscato A.A. Osipov A.N. Belikova N.A. Kapralov A.A. Kini V. Vlasova I.I. Zhao Q. Zou M. Di P. Svistunenko D.A. Kurnikov I.V. Borisenko G.G. Nat. Chem. Biol. 2005; 1: 223-232Crossref PubMed Scopus (982) Google Scholar, 28Podrez E.A. Schmitt D. Hoff H.F. Hazen S.L. J. Clin. 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Over the past several years, much effort has focused on our understanding of the chemical and structural nature of oxPL ligands recognized by macrophage pattern recognition receptors. There is general consensus that a significant portion of ligand binding activity on oxidized lipoproteins and senescent or apoptotic cells resides within extractable lipids (33Podrez E.A. Febbraio M. Sheibani N. Schmitt D. Silverstein R.L. Hajjar D.P. Cohen P.A. Frazier W.A. Hoff H.F. Hazen S.L. J. Clin. Investig. 2000; 105: 1095-1108Crossref PubMed Scopus (364) Google Scholar, 34Boullier A. Gillotte K.L. Horkko S. Green S.R. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Quehenberger O. J. Biol. Chem. 2000; 275: 9163-9169Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 35Bird D.A. Gillotte K.L. Horkko S. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6347-6352Crossref PubMed Scopus (108) Google Scholar, 36Boullier A. Bird D.A. Chang M.K. Dennis E.A. Friedman P. Gillotre-Taylor K. Horkko S. Palinski W. Quehenberger O. Shaw P. Steinberg D. Terpstra V. Witztum J.L. Ann. N. Y. Acad. Sci. 2001; 947 (Discussion 222–213): 214-222Crossref PubMed Scopus (244) Google Scholar, 37Terpstra V. Bird D.A. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1806-1811Crossref PubMed Scopus (75) Google Scholar). For example, studies from the collaborative research groups of Steinberg and Witztum (35Bird D.A. Gillotte K.L. Horkko S. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6347-6352Crossref PubMed Scopus (108) Google Scholar) first reported that receptors for oxLDL on elicited mouse peritoneal macrophages recognize both the oxidized lipid component and the modified protein moieties of oxLDL. In an extension of those studies, these investigators later identified the mouse scavenger receptor CD36 responsible for mediating binding to copper oxLDL via oxPC (34Boullier A. Gillotte K.L. Horkko S. Green S.R. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Quehenberger O. J. Biol. Chem. 2000; 275: 9163-9169Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). In competition studies ∼50% of the CD36 binding activity was shown to reside within the lipid (organic solvent)-extractable fraction (34Boullier A. Gillotte K.L. Horkko S. Green S.R. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Quehenberger O. J. Biol. Chem. 2000; 275: 9163-9169Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). Concurrently, Podrez et al. (33Podrez E.A. Febbraio M. Sheibani N. Schmitt D. Silverstein R.L. Hajjar D.P. Cohen P.A. Frazier W.A. Hoff H.F. Hazen S.L. J. Clin. Investig. 2000; 105: 1095-1108Crossref PubMed Scopus (364) Google Scholar) reported results from studies employing LDL exposed to the myeloperoxidase-H2O2-nitrite system of monocytes, a more physiologically relevant oxidized form of LDL. Here, the vast majority of macrophage recognition of the oxidatively modified lipoprotein was shown to reside within the lipid-extractable portion of the particle, with >90% of the binding attributable to oxPC interaction with macrophage scavenger receptor CD36 (33Podrez E.A. Febbraio M. Sheibani N. Schmitt D. Silverstein R.L. Hajjar D.P. Cohen P.A. Frazier W.A. Hoff H.F. Hazen S.L. J. Clin. Investig. 2000; 105: 1095-1108Crossref PubMed Scopus (364) Google Scholar). In studies with copper oxLDL, at least half of the macrophage binding activity was observed to remain in the protein moieties of lipoprotein following solvent extraction, suggesting that protein-oxPL adducts may also serve as ligands for macrophage recognition and phagocytosis via CD36 (34Boullier A. Gillotte K.L. Horkko S. Green S.R. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Quehenberger O. J. Biol. Chem. 2000; 275: 9163-9169Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). 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Laurila A. Hörkkö S. Han K.H. Friedman P. Dennis E.A. Witztum J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6353-6358Crossref PubMed Scopus (396) Google Scholar, 38Chang M.K. M. Witztum J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: PubMed Scopus Google Scholar). has been the several in of oxidized glycerophospholipids that macrophage recognition of oxLDL and and apoptotic cell Podrez et al. E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Gugiu B. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. Silverstein R.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) reported the first at identifying the of oxidized lipids that serve as ligands for the scavenger receptor with species critical structural of ligands for CD36 that high affinity binding to the scavenger a phospholipid with a sn-2 acyl group that incorporates a terminal γ-hydroxy(or oxo)-α,β-unsaturated E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Gugiu B. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. Silverstein R.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the oxidized lipid ligands of CD36 are in PC molecular as studies shown that of phospholipids and the high affinity for CD36 recognition and phagocytosis (19Greenberg M.E. Sun M. Zhang R. Febbraio M. Silverstein R. Hazen S.L. J. Exp. Med. 2006; 203: 2613-2625Crossref PubMed Scopus (319) Google Scholar, M. Finnemann S.C. Febbraio M. Shan L. Annangudi S.P. Podrez E.A. Hoppe G. Darrow R. Organisciak D.T. Salomon R.G. Silverstein R.L. Hazen S.L. J. Biol. Chem. 2006; 281: 4222-4230Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, M.E. Li X.M. Gugiu B.G. Gu X. Qin J. Salomon R.G. Hazen S.L. J. Biol. Chem. 2008; 283: 2385-2396Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Gugiu B. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. Silverstein R.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The of identified a of cell binding studies and and in with results of numerous to functional groups on of of that upon results and of lipid oxidation and and de of oxidized The of the oxidation and by that species MS, and of the lipids from oxidized oxidized and oxidized (19Greenberg M.E. Sun M. Zhang R. Febbraio M. Silverstein R. Hazen S.L. J. Exp. Med. 2006; 203: 2613-2625Crossref PubMed Scopus (319) Google Scholar, M. Finnemann S.C. Febbraio M. Shan L. Annangudi S.P. Podrez E.A. Hoppe G. Darrow R. Organisciak D.T. Salomon R.G. Silverstein R.L. Hazen S.L. J. Biol. Chem. 2006; 281: 4222-4230Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, M.E. Li X.M. Gugiu B.G. Gu X. Qin J. Salomon R.G. Hazen S.L. J. Biol. Chem. 2008; 283: 2385-2396Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Gugiu B. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. Silverstein R.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the of these species in lipoproteins oxidized by pathways in E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Gugiu B. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), in atherosclerotic in vivo E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. Silverstein R.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), in following in (20Sun M. Finnemann S.C. Febbraio M. Shan L. Annangudi S.P. Podrez E.A. Hoppe G. Darrow R. Organisciak D.T. Salomon R.G. Silverstein R.L. Hazen S.L. J. Biol. Chem. 2006; 281: 4222-4230Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), and in following S. Zhang R. M.E. Sun M. Chen X. Salomon R.G. Hazen S.L. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Google Scholar). of oxidized glycerophospholipids in the in vivo that been shown to be generated by of many been reported to P.S. Imura M. Zhang B. Gharavi N.M. Clark M.J. Pagnon J. Yang W.P. He A. Truong A. Patel S. Nelson S.F. Horvath S. Berliner J.A. Kirchgessner T.G. Lusis A.J. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 12741-12746Crossref PubMed Scopus (273) Google Scholar) or when to proteins may scavenger receptor recognition (34Boullier A. Gillotte K.L. Horkko S. Green S.R. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Quehenberger O. J. Biol. Chem. 2000; 275: 9163-9169Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar), with high affinity to CD36 when in membranes as oxPL E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Gugiu B. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. Silverstein R.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). pathways responsible for and of is in In studies confirm the of pathways to E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Gugiu B. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The pathways shown of lipid or of species recent studies by and J. Kini V. Belikova N. Borisenko G.G. Tyurina Y.Y. Tyurin V.A. V.E. 2004; Scopus Google Scholar, Tyurina Y.Y. Tyurin V.A. V.E. Biol. 2005; Google Scholar) reported that oxidation and of during of apoptotic are following of lipid of by or an The of within membranes can recognition and when at a E.A. Poliakov E. Zhang R. Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. Silverstein R.L. Hoff H.F. Salomon R.G. Hazen S.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of may be for the oxidized lipids also For example, oxidation to of more oxidized and can the oxidized lipids may serve as for phospholipase as for Prescott S.M. McIntyre T.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Prescott S.M. Zimmerman G.A. McIntyre T.M. J. Biol. Chem. 1989; Full Text PDF PubMed Google Scholar). This sn-2 fatty acids from oxPC membrane remodeling and of oxPL A of are of as of proteins and a of molecular species possessing fatty acyl can a and to form oxPL species possessing an sn-2 acyl group that incorporates a terminal S. Zhang R. M.E. Sun M. Chen X. Salomon R.G. Hazen S.L. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Google Scholar). In to to CD36 and to trigger phagocytosis S. Zhang R. M.E. Sun M. Chen X. Salomon R.G. Hazen S.L. J. Biol. 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Immunol. 2002; PubMed Scopus Google Scholar) to support the that oxidation of occurs during via activity of by in a recent of studies, et al. (19Greenberg M.E. Sun M. Zhang R. Febbraio M. Silverstein R. Hazen S.L. J. Exp. Med. 2006; 203: 2613-2625Crossref PubMed Scopus (319) Google Scholar) that binding and of are by A critical role for species in apoptotic cell recognition by macrophage CD36 was by of shown to to cells, studies employing and CD36 peritoneal macrophages a for oxidation of for cell binding and phagocytosis via CD36 in macrophages (19Greenberg M.E. Sun M. Zhang R. Febbraio M. Silverstein R. Hazen S.L. J. Exp. Med. 2006; 203: 2613-2625Crossref PubMed Scopus (319) Google Scholar). of into cell membranes was shown to CD36 binding activity and to be by studies employing cells and apoptotic a critical role for as a recognition ligand for with that species possessing the CD36 recognition are within apoptotic membranes and may a role in recognition of apoptotic cells (19Greenberg M.E. Sun M. Zhang R. Febbraio M. Silverstein R. Hazen S.L. J. Exp. Med. 2006; 203: 2613-2625Crossref PubMed Scopus (319) Google Scholar). Recent studies into the conformation of oxPL species recognized by CD36 within model membranes (22Greenberg M.E. Li X.M. Gugiu B.G. Gu X. Qin J. Salomon R.G. Hazen S.L. J. Biol. Chem. 2008; 283: 2385-2396Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 24Li X.M. Salomon R.G. Qin J. Hazen S.L. Biochemistry. 2007; 46: 5009-5017Crossref PubMed Scopus (39) Google Scholar) to the development of the Lipid Whisker Model (22Greenberg M.E. Li X.M. Gugiu B.G. Gu X. Qin J. 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The conformation of the lipids the following as cell membranes lipid as during or hydrophobic of fatty acids will from the interior of lipid to the aqueous This conformational may physical contact between pattern recognition receptor and molecular pattern ligand. the of the cell membranes will as phospholipids and many of oxidized fatty acids at the surface of the Lipid Whisker Cell membranes of senescent or apoptotic cells oxPL with a of oxidized fatty acyl of into the aqueous This conformation to with scavenger receptors and other pattern recognition receptors on the surface of macrophages of the innate immune It may also more for some membrane remodeling as oxidized fatty acids are and This was from M.E. Li X.M. Gugiu B.G. Gu X. Qin J. Salomon R.G. Hazen S.L. J. Biol. 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It is to that the of these is to the conformational of the oxidized sn-2 fatty species within a membrane been in the diverse molecular species of lipids that within a membrane and the of lipid can a array of the and of important in and has this and diverse for innate immune recognition and important chemical groups and to serve as shared molecular patterns for of and oxidatively modified cells, lipoproteins, apoptotic cells, and cellular patterns on the surface of innate immune functions of host with surveillance oxPL that chemical and pattern recognition a system for molecular pattern recognition as in the Lipid Whisker studies are to to both chemical and conformational within on the surface of membranes and lipoproteins and receptors