The role of HDL in innate immunity

Abstract

HDL has anti-atherogenic properties that are primarily attributed to its key role in reverse cholesterol transport. The ability of HDL to inhibit the oxidation of LDL, decrease inflammation, inhibit thrombosis, stimulate fibrinolysis, and favorably affect endothelial cell function may also contribute to the anti-atherogenic effects of HDL (1Ansell B.J. Watson K.E. Fogelman A.M. Navab M. Fonarow G.C. High-density lipoprotein function recent advances.J. Am. Coll. Cardiol. 2005; 46: 1792-1798Crossref PubMed Scopus (231) Google Scholar, 2Tall A.R. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.J. Intern. Med. 2008; 263: 256-273Crossref PubMed Scopus (335) Google Scholar). Not well recognized is the role HDL plays in innate immunity (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). Numerous studies have shown that lipoproteins bind microorganisms or compounds derived from microorganisms (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). When either endotoxin (LPS), from gram negative bacteria, or lipoteichoic acid (LTA), from gram positive bacteria, are incubated with whole blood from healthy humans, the majority of the LPS and LTA are bound to HDL. This binding to HDL inhibits the ability of LPS and LTA to interact with toll-like receptors (TLR) and activate macrophages (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). TLR activation of macrophages stimulates the production and secretion of cytokines and other signaling molecules, which if produced in excess can lead to septic shock and death (4Beutler B. Hoebe K. Du X. Ulevitch R.J. How we detect microbes and respond to them: the Toll-like receptors and their transducers.J. Leukoc. Biol. 2003; 74: 479-485Crossref PubMed Scopus (499) Google Scholar, 5Parrillo J.E. Pathogenetic mechanisms of septic shock.N. Engl. J. Med. 1993; 328: 1471-1477Crossref PubMed Scopus (1502) Google Scholar). In addition to binding LPS, studies have shown that HDL also facilitates the release of LPS that is already bound to macrophages, reducing macrophage activation (6Kitchens R.L. Wolfbauer G. Albers J.J. Munford R.S. Plasma lipoproteins promote the release of bacterial lipopolysaccharide from the monocyte cell surface.J. Biol. Chem. 1999; 274: 34116-34122Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Transgenic mice overexpressing apolipoprotein A-I have elevations in serum HDL levels and are protected from death due to LPS and severe bacterial infection (7Levine D.M. Parker T.S. Donnelly T.M. Walsh A. Rubin A.L. In vivo protection against endotoxin by plasma high density lipoprotein.Proc. Natl. Acad. Sci. USA. 1993; 90: 12040-12044Crossref PubMed Scopus (425) Google Scholar). Similarly, several studies have shown that infusion of HDL or apolipoprotein A-I mimetic peptides into animals with experimental sepsis improves survival (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar, 8Hubsch A.P. Casas A.T. Doran J.E. Protective effects of reconstituted high-density lipoprotein in rabbit gram-negative bacteremia models.J. Lab. Clin. Med. 1995; 126: 548-558PubMed Google Scholar, 9Zhang Z. Datta G. Zhang Y. Miller A.P. Mochon P. Chen Y.F. Chatham J. Anantharamaiah G.M. White C.R. Apolipoprotein A-I mimetic peptide treatment inhibits inflammatory responses and improves survival in septic rats.Am. J. Physiol. 2009; 297: H866-H873Crossref PubMed Scopus (56) Google Scholar). Conversely, reducing serum lipoprotein levels increases the ability of LPS administration to induce death and this increased susceptibility can be reversed by providing exogenous lipoproteins (10Feingold K.R. Funk J.L. Moser A.H. Shigenaga J.K. Rapp J.H. Grunfeld C. Role for circulating lipoproteins in protection from endotoxin toxicity.Infect. Immun. 1995; 63: 2041-2046Crossref PubMed Google Scholar). Humans with low HDL levels have a more robust inflammatory response to LPS administration (11Birjmohun R.S. van Leuven S.I. Levels J.H. van ‘t Veer C. Kuivenhoven J.A. Meijers J.C. Levi M. Kastelein J.J. van der Poll T. Stroes E.S. High-density lipoprotein attenuates inflammation and coagulation response on endotoxin challenge in humans.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1153-1158Crossref PubMed Scopus (96) Google Scholar). Furthermore, the administration of reconstituted HDL to humans blunts the deleterious effects of LPS administration (12Pajkrt D. Doran J.E. Koster F. Lerch P.G. Arnet B. van der Poll T. ten Cate J.W. van Deventer S.J. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia.J. Exp. Med. 1996; 184: 1601-1608Crossref PubMed Scopus (343) Google Scholar). In addition to binding bacterial products, HDL also binds a wide variety of viruses and neutralizes their activity (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). Moreover, HDL also plays a protective role in parasitic infections (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). The lysis of trypanosomes is mediated by HDL particles that contain apolipoprotein L1 and haptoglobin-related protein (13Pays E. Vanhollebeke B. Human innate immunity against African trypanosomes.Curr. Opin. Immunol. 2009; 21: 493-498Crossref PubMed Scopus (48) Google Scholar). Additionally, recent studies have shown that apolipoprotein L1 and haptoglobin-related protein also inhibit infection by Leishmania (14Samanovic M. Molina-Portela M.P. Chessler A.D. Burleigh B.A. Raper J. Trypanosome lytic factor, an antimicrobial high-density lipoprotein, ameliorates Leishmania infection.PLoS Pathog. 2009; 5: e1000276Crossref PubMed Scopus (62) Google Scholar). Finally, low levels of HDL and apolipoprotein A-I are associated with an increase in mortality in patients admitted to intensive care units (15Barlage S. Gnewuch C. Liebisch G. Wolf Z. Audebert F.X. Gluck T. Frohlich D. Kramer B.K. Rothe G. Schmitz G. Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation.Intensive Care Med. 2009; 35: 1877-1885Crossref PubMed Scopus (96) Google Scholar–17Grion C.M. Cardoso L.T. Perazolo T.F. Garcia A.S. Barbosa D.S. Morimoto H.K. Matsuo T. Carrilho A.J. Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients.Eur. J. Clin. Invest. 2010; 40: 330-338Crossref PubMed Scopus (65) Google Scholar). Taken together, these observations indicate that HDL plays a role in protecting the host from the toxic effects of microorganisms and is part of the innate immune system. The structural basis for the protective effects of HDL has been studied most intensively for LPS. Both the lipid and proteins that comprise HDL contribute to the neutralization of LPS. Apolipoprotein A-I alone can neutralize LPS and this interaction can be altered by changing the structure of apolipoprotein A-I (18Wang Y. Zhu X. Wu G. Shen L. Chen B. Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice.J. Lipid Res. 2008; 49: 1640-1645Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). For example, serine substitution of one cysteine (228) in the C-terminal domain dramatically reduces the ability of HDL to neutralize LPS, whereas substitutions of other cysteines (52 or 74) enhance the ability of HDL to neutralize LPS (18Wang Y. Zhu X. Wu G. Shen L. Chen B. Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice.J. Lipid Res. 2008; 49: 1640-1645Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). The amino acid substitutions that affect LPS neutralization have minimal effects on the lipid composition of HDL. However, lipid emulsions devoid of protein can also neutralize LPS, demonstrating that lipids also play a key role (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). The phospholipid content of lipoproteins correlates with the ability of lipoproteins to neutralize LPS, whereas the content of cholesterol or triglycerides does not (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). Additionally, phospholipids alone have been shown to protect animals from LPS-induced toxicity. Thus, both apolipoproteins and phospholipids can play important roles in the ability of HDL to neutralize LPS (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). In this issue, Hara et al. (19Hara T. Ishida T. Kojima Y. Tanaka H. Yasuda T. Shinohara M. Toh R. Hirata K.I. Targeted deletion of endothelial lipase increases HDL particles with anti-inflammatory properties both in vitro and in vivo.J. Lipid Res. 2011; 52: 57-67Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar) explore the effect of endothelial lipase deficiency on the function of HDL particles. They report that HDL isolated from endothelial lipase knockout mice is similar to HDL isolated from wild-type mice in the ability to facilitate cholesterol efflux, protect from oxidation, and inhibit the ability of cytokines to activate endothelial cells. However, they demonstrate that HDL from endothelial lipase knockout mice are more potent in neutralizing LPS than control HDL in vitro and in vivo. Specifically, they show that 1) HDL from endothelial lipase knockout mice is more effective than control HDL in inhibiting the ability of LPS to stimulate tumor necrosis factor secretion by macrophages in vitro, 2) Endothelial lipase knockout mice are resistent to LPS-induced death and the LPS-induced increase in plasma cytokine levels is blunted, and 3) the administration of HDL from endothelial lipase knockout mice protects wild-type mice from LPS induced toxicity more effectively than the administration of wild-type HDL. Endothelial lipase is well known to preferentially metabolize phospholipids on HDL. Similar to previous reports, Hara et al. demonstrate that the phospholipid content of HDL from endothelial lipase knockout mice is increased and that the increased protection from LPS-induced toxicity is proportional to the increase in phospholipids rather than an increase in HDL protein. Thus, the studies of Hara et al. clearly demonstrate that endothelial lipase deficiency results in HDL particles that function similar to or even better than control HDL. Whether raising HDL levels by inhibiting endothelial lipase activity will favorably affect atherosclerosis is unclear. Using endothelial lipase knockout mice, one group has shown a reduction in atherosclerosis in apolipoprotein E deficient/ endothelial lipase double knockout mice, whereas another group has reported no effect in either apolipoprotein E deficient or LDL receptor deficient mice (20Ishida T. Choi S.Y. Kundu R.K. Spin J. Yamashita T. Hirata K. Kojima Y. Yokoyama M. Cooper A.D. Quertermous T. Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice.J. Biol. Chem. 2004; 279: 45085-45092Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 21Ko K.W. Paul A. Ma K. Li L. Chan L. Endothelial lipase modulates HDL but has no effect on atherosclerosis development in apoE−/− and LDLR−/− mice.J. Lipid Res. 2005; 46: 2586-2594Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). From the point of view of host defense, it should be noted that inflammation, induced by either LPS or cytokines, has been shown to increase endothelial lipase expression (22Kojma Y. Hirata K. Ishida T. Shimokawa Y. Inoue N. Kawashima S. Quertermous T. Yokoyama M. Endothelial lipase modulates monocyte adhesion to the vessel wall. A potential role in inflammation.J. Biol. Chem. 2004; 279: 54032-54038Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar–25Wang X. Jin W. Rader D.J. Upregulation of macrophage endothelial lipase by toll-like receptors 4 and 3 modulates macrophage interleukin-10 and -12 production.Circ. Res. 2007; 100: 1008-1015Crossref PubMed Scopus (23) Google Scholar). The endothelial lipase promoter contains a nuclear factor kB (NFkB) response element and LPS induces an increase in binding to that site (26Wu X. Huang H. Tang F. Le K. Xu S. Liu P. Regulated expression of endothelial lipase in atherosclerosis.Mol. Cell. Endocrinol. 2010; 315: 233-238Crossref PubMed Scopus (27) Google Scholar). Suppression of NFkB activation with inhibitors blocks the increase in endothelial lipase expression induced by LPS (26Wu X. Huang H. Tang F. Le K. Xu S. Liu P. Regulated expression of endothelial lipase in atherosclerosis.Mol. Cell. Endocrinol. 2010; 315: 233-238Crossref PubMed Scopus (27) Google Scholar). Thus, during infection and inflammation, endothelial lipase increases and one could speculate that this would result in a reduction in the ability of HDL to neutralize LPS. In fact, studies have shown that although HDL is the lipoprotein primarily responsible for the binding of LPS in the basal state, during infections and inflammation, the role of HDL decreases and VLDL assumes the major role in LPS neutralization due to both structural changes in VLDL and an increase in VLDL levels (3Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar, 27Kitchens R.L. Thompson P.A. Impact of sepsis-induced changes in plasma on LPS interactions with monocytes and plasma lipoproteins: roles of soluble CD14, LBP, and acute phase lipoproteins.J. Endotoxin Res. 2003; 9: 113-118Crossref PubMed Scopus (39) Google Scholar). Finally, from a broader perspective, as drugs are developed to raise HDL levels, one will need to determine the effectiveness of these drugs not only on their ability to stimulate reverse cholesterol transport and reduce atherosclerosis, but also on their ability to affect the other protective functions of HDL. It is notable that in the large randomized trial of torcetrapib, there was a marked increase in deaths due to infectious disease in the group treated with the CETP inhibitor (28Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2591) Google Scholar). Whether this was a chance observation or resulted from alterations in HDL structure and function is unknown, but needs to be addressed in future studies. Targeted deletion of endothelial lipase increases HDL particles with anti-inflammatory properties both in vitro and in vivoJournal of Lipid ResearchVol. 52Issue 1PreviewPrevious studies have shown that targeted deletion of endothelial lipase (EL) markedly increases the plasma high density lipoprotein cholesterol (HDL-C) level in mice. However, little is known about the functional quality of HDL particles after EL inhibition. Therefore, the present study assessed the functional quality of HDL isolated from EL−/− and wild-type (WT) mice. Anti-inflammatory functions of HDL from EL−/− and WT mice were evaluated by in vitro assays. The HDL functions such as PON-1 or PAF-AH activities, inhibition of cytokine-induced vascular cell adhesion molecule-1 expression, inhibition of LDL oxidation, and the ability of cholesterol efflux were similar in HDL isolated from WT and EL−/− mice. Full-Text PDF Open Access