Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL

Tissue cholesterol accumulation, macrophage infiltration, and inflammation are features of atherosclerosis and some forms of dermatitis. HDL and its main protein, apoAI, are acceptors of excess cholesterol from macrophages; this process inhibits tissue inflammation. Recent epidemiologic and clinical trial evidence questions the role of HDL and its manipulation in cardiovascular disease. We investigated the effect of ectopic macrophage apoAI expression on atherosclerosis and dermatitis induced by the combination of hypercholesterolemia and absence of HDL in mice. Hematopoietic progenitor cells were transduced to express human apoAI and transplanted into lethally irradiated LDL receptor−/−/apoAI−/− mice, which were then placed on a high-fat diet for 16 weeks. Macrophage apoAI expression reduced aortic CD4+ T-cell levels (−39.8%), lesion size (−25%), and necrotic core area (−31.6%), without affecting serum HDL or aortic macrophage levels. Macrophage apoAI reduced skin cholesterol by 39.8%, restored skin morphology, and reduced skin CD4+ T-cell levels. Macrophage apoAI also reduced CD4+ T-cell levels (−32.9%) in skin-draining lymph nodes but had no effect on other T cells, B cells, dendritic cells, or macrophages compared with control transplanted mice. Thus, macrophage apoAI expression protects against atherosclerosis and dermatitis by reducing cholesterol accumulation and regulating CD4+ T-cell levels, without affecting serum HDL or tissue macrophage levels. Tissue cholesterol accumulation, macrophage infiltration, and inflammation are features of atherosclerosis and some forms of dermatitis. HDL and its main protein, apoAI, are acceptors of excess cholesterol from macrophages; this process inhibits tissue inflammation. Recent epidemiologic and clinical trial evidence questions the role of HDL and its manipulation in cardiovascular disease. We investigated the effect of ectopic macrophage apoAI expression on atherosclerosis and dermatitis induced by the combination of hypercholesterolemia and absence of HDL in mice. Hematopoietic progenitor cells were transduced to express human apoAI and transplanted into lethally irradiated LDL receptor−/−/apoAI−/− mice, which were then placed on a high-fat diet for 16 weeks. Macrophage apoAI expression reduced aortic CD4+ T-cell levels (−39.8%), lesion size (−25%), and necrotic core area (−31.6%), without affecting serum HDL or aortic macrophage levels. Macrophage apoAI reduced skin cholesterol by 39.8%, restored skin morphology, and reduced skin CD4+ T-cell levels. Macrophage apoAI also reduced CD4+ T-cell levels (−32.9%) in skin-draining lymph nodes but had no effect on other T cells, B cells, dendritic cells, or macrophages compared with control transplanted mice. Thus, macrophage apoAI expression protects against atherosclerosis and dermatitis by reducing cholesterol accumulation and regulating CD4+ T-cell levels, without affecting serum HDL or tissue macrophage levels. Serum levels of HDL and its major protein apoAI are associated with decreased coronary heart disease (CHD) rates (1Castelli W.P. Garrison R.J. Wilson P.W. Abbott R.D. Kalousdian S. Kannel W.B. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study.J. Am. Med. Assoc. 1986; 256: 2835-2838Crossref PubMed Scopus (2080) Google Scholar, 2Assmann G. Cullen P. Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years.Eur. Heart J. 1998; 19: A2-11PubMed Google Scholar). Antiatherogenic properties of HDL and apoAI are attributed to their reverse cholesterol transport capacity and anti-inflammatory effects (3Rosenson R.S. Brewer Jr, H.B. Davidson W.S. Fayad Z.A. Fuster V. Goldstein J. Hellerstein M. Jiang X.C. Phillips M.C. Rader D.J. et al.Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.Circulation. 2012; 125: 1905-1919Crossref PubMed Scopus (681) Google Scholar, 4Maxfield F.R. Tabas I. Role of cholesterol and lipid organization in disease.Nature. 2005; 438: 612-621Crossref PubMed Scopus (969) Google Scholar). However, there is evidence that some causes of low HDL are atheroprotective (5Sirtori C.R. Calabresi L. Franceschini G. Baldassarre D. Amato M. Johansson J. Salvetti M. Monteduro C. Zulli R. Muiesan M.L. et al.Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study.Circulation. 2001; 103: 1949-1954Crossref PubMed Scopus (301) Google Scholar) and that very high HDL levels may not be associated with cardiovascular protection (6Hirano K. Yamashita S. Kuga Y. Sakai N. Nozaki S. Kihara S. Arai T. Yanagi K. Takami S. Menju M. et al.Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1849-1856Crossref PubMed Scopus (149) Google Scholar). These observations are supported by results of recent clinical trials reporting absence of cardiovascular benefits with pharmacologic maneuvers to increase HDL levels (7Kingwell B.A. Chapman M.J. Kontush A. Miller N.E. HDL-targeted therapies: progress, failures and future.Nat. Rev. Drug Discov. 2014; 13: 445-464Crossref PubMed Scopus (262) Google Scholar, 8Mohammadpour A.H. Akhlaghi F. Future of cholesteryl ester transfer protein (CETP) inhibitors: a pharmacological perspective.Clin. Pharmacokinet. 2013; 52: 615-626Crossref PubMed Scopus (59) Google Scholar). Thus, changes in serum HDL-cholesterol levels may not be a representation of the atheroprotective role of HDL (9Rader D.J. Hovingh G.K. HDL and cardiovascular disease.Lancet. 2014; 384: 618-625Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar). These data compel an investigation of the precise role of HDL and apoAI in tissue cholesterol homeostasis and in the regulation of the inflammatory response driven by cholesterol accumulation. ApoAI is naturally expressed in hepatocytes and enterocytes but not in peripheral cells, including macrophages. Yet, apoAI is critical for the unloading of cholesterol from macrophages, with pathologic and clinical consequences ranging from atherosclerosis to xanthomatosis and skin inflammation (10Rader D.J. Alexander E.T. Weibel G.L. Billheimer J. Rothblat G.H. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis.J. Lipid Res. 2009; 50: S189-S194Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar). We and other groups have shown that ectopic expression of apoAI by macrophages (through transplantation of bone marrow cells transduced to express apoAI or derived from apoAI transgenic donors) reduces atherosclerosis by stimulating local cholesterol efflux (11Wang L. Sharifi B.G. Pan T. Song L. Yukht A. Shah P.K. Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice.J. Am. Coll. Cardiol. 2006; 48: 1459-1468Crossref PubMed Scopus (52) Google Scholar, 12Major A.S. Dove D.E. Ishiguro H. Su Y.R. Brown A.M. Liu L. Carter K.J. Linton M.F. Fazio S. Increased cholesterol efflux in apolipoprotein AI (ApoAI)-producing macrophages as a mechanism for reduced atherosclerosis in ApoAI((−/−)) mice.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1790-1795Crossref PubMed Scopus (44) Google Scholar, 13Ishiguro H. Yoshida H. Major A.S. Zhu T. Babaev V.R. Linton M.F. Fazio S. Retrovirus-mediated expression of apolipoprotein A-I in the macrophage protects against atherosclerosis in vivo.J. Biol. Chem. 2001; 276: 36742-36748Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Removal of cholesterol from the aortic wall was mediated through increasing local apoAI concentration and upregulation of cellular cholesterol transporters (14Su Y.R. Ishiguro H. Major A.S. Dove D.E. Zhang W. Hasty A.H. Babaev V.R. Linton M.F. Fazio S. Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters.Mol. Ther. 2003; 8: 576-583Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). In addition, both endogenous and exogenous apoAI were shown to stimulate the secretion of macrophage apoE, another physiological driver of cholesterol efflux (15Bielicki J.K. McCall M.R. Forte T.M. Apolipoprotein A-I promotes cholesterol release and apolipoprotein E recruitment from THP-1 macrophage-like foam cells.J. Lipid Res. 1999; 40: 85-92Abstract Full Text Full Text PDF PubMed Google Scholar, 16Kockx M. Rye K.A. Gaus K. Quinn C.M. Wright J. Sloane T. Sviridov D. Fu Y. Sullivan D. Burnett J.R. et al.Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux.J. Biol. Chem. 2004; 279: 25966-25977Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 17Su Y.R. Blakemore J.L. Zhang Y. Linton M.F. Fazio S. Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1439-1446Crossref PubMed Scopus (18) Google Scholar). Together, lipid-free apoAI, HDL-bound apoAI, and apoE act in synergy to extract cholesterol from macrophages, thus influencing both macrophage cholesterol accumulation, a hallmark of atherosclerosis, and macrophage to local inflammatory M.F. Fazio S. and J. 2003; PubMed Scopus Google Scholar, A. Chapman M.J. a at the of and Rev. 2006; PubMed Scopus Google Scholar). macrophage and exogenous apoAI expression also expression by macrophages and the to an anti-inflammatory macrophage (11Wang L. Sharifi B.G. Pan T. Song L. Yukht A. Shah P.K. Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice.J. Am. Coll. Cardiol. 2006; 48: 1459-1468Crossref PubMed Scopus (52) Google Scholar, W. effects of AI are mediated macrophage 2014; Google Scholar, K. G.H. D. Fu Jiang et al.Apolipoprotein A-I inhibits atherosclerosis in mice upregulation of 2013; PubMed Scopus Google Scholar). In to atherosclerosis, with reverse cholesterol transport skin inflammation local accumulation of cholesterol 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). with a inflammatory were shown to have levels of cholesterol in their skin compared with A. P. A. S. and cholesterol of the skin of with 1998; PubMed Scopus Google Scholar). that skin cholesterol levels into the and of atherosclerosis S. J. L. M. Abbott D. of skin cholesterol by a with of inflammation and Framingham J. Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar). of skin cholesterol accumulation to cholesterol efflux capacity is the LDL M. M. H. M. M. M.J. and skin cholesterol in cholesterol homeostasis and Lipid Res. 48: Full Text Full Text PDF PubMed Scopus Google Scholar). a accumulation of cholesterol in the skin of mice causes dermatitis M. S. T. M.J. Alexander M. M. of inflammation in LDL and mice and J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). mice also inflammation with as and lymph nodes and an CD4+ T-cell response M. Shah D. Major A.S. S. Jr, M.J. Apolipoprotein A-I T cells in mice.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). expression and of apoAI to mice from the dermatitis by reducing skin cholesterol accumulation and inflammation M. Shah D. Major A.S. S. Jr, M.J. Apolipoprotein A-I T cells in mice.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Major A.S. J. M. R. L. K. et al.Apolipoprotein A-I and its role in cholesterol homeostasis and Thromb. Vasc. Biol. 2009; PubMed Scopus Google Scholar). and skin lesion and inflammation are driven by local accumulation of macrophages, to expression of apoAI from macrophages is to mice from the of dermatitis and to its effects on and inflammatory We have mice apoAI from macrophages transduction of hematopoietic progenitor cells by their transplantation into mice both and results a in which the expression of macrophage apoAI protects against atherosclerosis and dermatitis both through of cholesterol from the aortic wall and and reduction of CD4+ T-cell levels in the aortic and skin-draining These effects of macrophage apoAI were not associated with changes in serum apoAI and HDL levels or tissue macrophage results that the of cholesterol in macrophages ectopic apoAI expression reduces atherosclerosis and the dermatitis of hyperlipidemic mice, thus a for the of a therapy of mice were from and at were an diet cholesterol with from in the diet of as M. S. T. M.J. Alexander M. M. of inflammation in LDL and mice and J. 2003; Full Text Full Text PDF PubMed Scopus Google and to the of were in a with a were in with of and were by the and of the and and The was and in as H. D. I. Zhu L. Linton M.F. Fazio S. atherosclerosis lipoprotein in hyperlipidemic mice.J. Lipid Res. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). In the and were by We have shown that transduction of with a protein the human in macrophages but not in B cells or T cells Y.R. Blakemore J.L. Zhang Y. Linton M.F. Fazio S. Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1439-1446Crossref PubMed Scopus (18) Google Scholar). The the was from human by The human apoAI with the was from an in Y.R. Blakemore J.L. Zhang Y. Linton M.F. Fazio S. Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1439-1446Crossref PubMed Scopus (18) Google Scholar). of the of the and apoAI was from of Y.R. Blakemore J.L. Zhang Y. Linton M.F. Fazio S. Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1439-1446Crossref PubMed Scopus (18) Google Scholar) and is shown in Bone marrow cells from to mice were from and were by of the cells with the cells were from the cells and to the were from or mice at 8 to of and then were transduced with or transduced with at a of the and for in transduction was or mice at to of were lethally irradiated with from a and transplanted with the apoAI transduced or and transduced as mice were on an diet cholesterol with from the of the mice were and their with in and in The was to the to of were in the of the from the of the aortic and for to the of et D. K. A. a gene atherosclerosis and high lipoprotein levels in PubMed Scopus Google Scholar). were with and with of was on at the of the aortic The were by and as area lesion were in the of the at the of the aortic and were in with in then with and with was to was in as Y.R. Blakemore J.L. Zhang Y. Linton M.F. Fazio S. Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1439-1446Crossref PubMed Scopus (18) Google Scholar). was in and and and by the area in the of lesion and and E were also aortic from the mice. and were and placed in were and as M. Shah D. Major A.S. S. Jr, M.J. Apolipoprotein A-I T cells in mice.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of was a and T cells T cells T cells B cells dendritic cells and macrophages in including and were from or were as M. S. T. M.J. Alexander M. M. of inflammation in LDL and mice and J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and other were the et D.E. of lipid in high and Lipid Res. Full Text PDF PubMed Google Scholar) and by skin skin were and into and were with or and were with or as M. Shah D. Major A.S. S. Jr, M.J. Apolipoprotein A-I T cells in mice.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were for 16 to Serum cholesterol or triglyceride were the or from were from serum by size a on a in H. D. Blakemore J.L. L. Linton M.F. Fazio S. Serum and cell lipoprotein evidence for a 2013; PubMed Scopus Google Scholar). ApoAI levels in mice serum were the Apolipoprotein AI from was to The was to data the Results are as or of are as and to mice were transplanted with apoAI and and compared with control mice transplanted with control and transplantation of levels of apoAI were to of physiological levels mice a diet for 16 serum cholesterol and in control and apoAI in and in apoAI and in and in apoAI and with low apoAI, expression of apoAI also not serum HDL or other lipoprotein levels in mice et M. Major A.S. J. M. R. L. K. et al.Apolipoprotein A-I and its role in cholesterol homeostasis and Thromb. Vasc. Biol. 2009; PubMed Scopus Google Scholar) that mice an diet a increase in the of atherosclerosis compared with mice. mice were and a of the of aortic atherosclerosis of the was The aortic lesion area of apoAI mice was that of control mice aortic of the are shown in apoAI mice a reduction in aortic lesion area compared with was shown that macrophage apoAI reduces the levels of inflammatory in the aortic lesion (11Wang L. Sharifi B.G. Pan T. Song L. Yukht A. Shah P.K. Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice.J. Am. Coll. Cardiol. 2006; 48: 1459-1468Crossref PubMed Scopus (52) Google Scholar, Y.R. Ishiguro H. Major A.S. Dove D.E. Zhang W. Hasty A.H. Babaev V.R. Linton M.F. Fazio S. Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters.Mol. Ther. 2003; 8: 576-583Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). and B lesion with apoAI mice in control and CD4+ in control cells in the of and in the are shown in ApoAI mice also a necrotic core area in the aortic lesion in control of the are in reduced CD4+ T cells and lesion size in apoAI the macrophage area in the aortic wall not compared with control mice In as a of area was in apoAI compared with of the are shown in were in the effects of macrophage apoAI expression on T cells, macrophages, and necrotic necrotic area of necrotic area of aortic lesion of mice 16 and diet 8 and 8 apoAI 8 and 8 of control and apoAI mice. mice cholesterol and inflammatory cells in the a inflammatory to M. S. T. M.J. Alexander M. M. of inflammation in LDL and mice and J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). results that apoAI mice levels of skin cholesterol compared with control mice and skin are in and apoAI mice a reduction in skin cholesterol levels compared with was shown that apoAI of T cells, macrophages, and in mice M. Major A.S. J. M. R. L. K. et al.Apolipoprotein A-I and its role in cholesterol homeostasis and Thromb. Vasc. Biol. 2009; PubMed Scopus Google Scholar). We that apoAI mice had levels of skin CD4+ T cells compared with In macrophage and of skin not apoAI and control mice, both compared with skin from mice on diet In skin-draining and there was no in the of cells apoAI or control mice However, skin-draining of apoAI mice a reduction in cells CD4+ cells and cells were in other T-cell as or T cells In addition, no were in B cell or macrophage levels in cells the major for HDL is the without a (7Kingwell B.A. Chapman M.J. Kontush A. Miller N.E. HDL-targeted therapies: progress, failures and future.Nat. Rev. Drug Discov. 2014; 13: 445-464Crossref PubMed Scopus (262) Google Scholar, on and of in of the of the on and of In J. Am. Med. Scholar). of the main of HDL and apoAI is to cholesterol efflux from peripheral cells in and macrophages in thus foam cell J. A. H. Y. as a of of in and in PubMed Scopus Google Scholar) and reducing inflammation K.J. in a Rev. 2013; 13: PubMed Scopus Google Scholar). capacity to efflux cholesterol from macrophages by HDL in serum is a for atherosclerosis in mice and humans C. G. N. N. et protects against atherosclerosis.J. PubMed Scopus Google Scholar, M. M. A. M.F. K. Phillips M.L. et al.Cholesterol efflux lipoprotein and J. Med. PubMed Scopus Google Scholar, Y. Y. W. V. D. et of cholesterol efflux with cardiovascular Thromb. Vasc. Biol. 2013; PubMed Scopus Google Scholar). of macrophage cholesterol efflux from macrophages gene of as atherosclerosis and causes accumulation of cholesterol and macrophage in the skin to dermatitis in mice M. Jr, Linton M.F. Fazio S. Jr, xanthomatosis and of in hyperlipidemic mice PubMed Scopus Google Scholar). The of dermatitis is also by the of in macrophages M. Jr, Linton M.F. Fazio S. Jr, xanthomatosis and of in hyperlipidemic mice PubMed Scopus Google Scholar). have also shown a skin cholesterol accumulation and atherosclerosis S. J. L. M. Abbott D. of skin cholesterol by a with of inflammation and Framingham J. Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar, R. M.J. P. C. M. for the of skin Chem. 2001; PubMed Scopus Google Scholar). investigated expression of apoAI from macrophages both atherosclerosis and dermatitis in mice of and absence of reverse cholesterol results a in which macrophage expression of apoAI cholesterol and CD4+ T-cell levels to atherosclerosis and the dermatitis without affecting serum and HDL levels or tissue macrophage The of was to the effects of macrophage apoAI expression in the aortic and skin-draining dermatitis and atherosclerosis are both by cellular cholesterol accumulation and apoAI expression is an for the control of both transplantation is a to the effect of of macrophage gene expression on atherosclerosis in the M. R. G. Bone marrow transplantation in mice as a for the role of hematopoietic cells in and cardiovascular Full Text Full Text PDF PubMed Scopus Google with applications for a therapy in humans H. Hematopoietic applications for 2014; Google Scholar). ApoAI to that of apoE C. V. N. Forte T.M. Phillips M.C. S. J.K. The of apolipoprotein E is a of cholesterol efflux that promotes the of PubMed Scopus Google macrophages not naturally apoAI and apoE to as the physiological driver of cholesterol efflux to foam cell D.E. Linton M.F. Fazio S. cholesterol efflux from macrophages: of and J. 2005; PubMed Scopus Google Scholar, P. N. and of macrophage cholesterol efflux.J. PubMed Scopus Google Scholar). atherosclerosis both by reducing serum lipid levels M.F. Fazio S. of atherosclerosis in apolipoprotein mice by bone marrow 1995; PubMed Scopus Google Scholar, M.F. Fazio S. lipoprotein and from bone marrow transplantation 1999; PubMed Scopus Google Scholar) and by local effects on the S. Babaev V.R. Hasty A.H. Carter K.J. Linton M.F. Increased atherosclerosis in mice with apolipoprotein E PubMed Scopus Google Scholar). In transgenic expression of apoAI from macrophages shown to in mice local effects and without serum lipid levels A.S. Dove D.E. Ishiguro H. Su Y.R. Brown A.M. Liu L. Carter K.J. Linton M.F. Fazio S. Increased cholesterol efflux in apolipoprotein AI (ApoAI)-producing macrophages as a mechanism for reduced atherosclerosis in ApoAI((−/−)) mice.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1790-1795Crossref PubMed Scopus (44) Google Scholar, 13Ishiguro H. Yoshida H. Major A.S. Zhu T. Babaev V.R. Linton M.F. Fazio S. Retrovirus-mediated expression of apolipoprotein A-I in the macrophage protects against atherosclerosis in vivo.J. Biol. Chem. 2001; 276: 36742-36748Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 17Su Y.R. Blakemore J.L. Zhang Y. Linton M.F. Fazio S. Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1439-1446Crossref PubMed Scopus (18) Google Scholar). In this mice transplanted with aortic lesion size compared with mice transplanted with control ApoAI expressed by in serum in low levels physiological low to serum or HDL levels. be that the of apoAI in the with and aortic may effects of atherosclerosis to atherosclerosis hematopoietic cell including macrophages, T cells, and K. and inflammatory of Rev. 2009; PubMed Scopus Google Scholar). of the local macrophage inflammatory response is to lesion Y. D. Blakemore J.L. Zhang Y. L. Zhang J. Linton M.F. Fazio S. lipoprotein protein atherosclerosis by and inflammatory evidence that the effects are not apolipoprotein E PubMed Scopus Google Scholar, M. S. T. N. M. M. S. C. et hematopoietic cell and accumulation in in mice.J. PubMed Scopus Google and apoAI macrophage and W. effects of AI are mediated macrophage 2014; Google Scholar, K. G.H. D. Fu Jiang et al.Apolipoprotein A-I inhibits atherosclerosis in mice upregulation of 2013; PubMed Scopus Google Scholar). data that macrophage apoAI local anti-inflammatory effects in the with reduced accumulation of and CD4+ T In addition, macrophage apoAI reduces the of necrotic core in the a of lesion T-cell recruitment and necrotic core are of aortic macrophage apoAI expression not macrophage area in the lipid is of for the and of the skin The the of lipid in the Lipid Res. 2009; 50: Full Text Full Text PDF PubMed Scopus Google Scholar). In with a disease by skin and of skin cholesterol levels are compared with A. P. A. S. and cholesterol of the skin of with 1998; PubMed Scopus Google Scholar). In addition, skin cholesterol levels with the of atherosclerosis by coronary coronary or S. J. L. M. Abbott D. of skin cholesterol by a with of inflammation and Framingham J. Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar). et M. M. Zhang N. Apolipoprotein E to foam cell in mice.J. 1995; Full Text PDF PubMed Scopus Google Scholar) have shown that skin in cholesterol and with features of inflammation are in mice with lipoprotein of skin cholesterol accumulation is serum cholesterol is and cholesterol efflux are M. Jr, Linton M.F. Fazio S. Jr, xanthomatosis and of in hyperlipidemic mice PubMed Scopus Google Scholar). of lipoprotein and cholesterol efflux is the which dermatitis on a high-fat diet M. S. T. M.J. Alexander M. M. of inflammation in LDL and mice and J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). that macrophage apoAI expression reduced skin cholesterol accumulation, restored skin morphology, and mice from their skin mice to skin as was by et M. S. T. M.J. Alexander M. M. of inflammation in LDL and mice and J. 2003; Full Text Full Text PDF PubMed Scopus Google apoAI skin at to the were mice of the shows that apoAI expressed by macrophages reduces and CD4+ T cell levels in the and CD4+ and CD4+ cells in skin-draining In macrophage apoAI expression not macrophages or other cells of the hematopoietic in the skin or skin-draining We that macrophage apoAI inhibits dermatitis and atherosclerosis through reduced cholesterol accumulation and regulation of CD4+ T cells in the aortic and skin-draining without affecting tissue macrophage or serum HDL and apoAI levels. results also that of apoAI by macrophages not macrophage recruitment into the aortic wall or skin by the lipid However, the reduced lipid of macrophages the tissue inhibits of inflammation and T-cell These results also that transplantation of may be as a therapy for of as with the of against with dendritic cell protein and hematopoietic progenitor cell LDL lymph