Recent Advances in the Role of Immunity in Atherosclerosis Gabrielle Fredman and Matthew Spite Circ Res. 2013;113:e111-e114 doi: 10.1161/CIRCRESAHA.113.302986 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/113/12/e111
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
Recent Developments Recent Developments in Cardiovascular Research: The goal of Recent Developments is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and impact of work performed in other fields. It is our hope and expectation that these Recent Developments articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research. — The Editors
Recent Advances in the Role of Immunity in Atherosclerosis Gabrielle Fredman, Matthew Spite
T
he immune system serves to protect the host from a diverse array of pathogens that evolve rapidly in an effort to breach immune security checkpoints. These defense mechanisms operate continuously to keep exogenous pathogens from propagating their own species, although this heightened security has unintended and detrimental consequences to the host.1 Although this maladaptive immune response is classically associated with noninfectious diseases, such as arthritis, gout, and lupus, uncontrolled inflammation is emerging as a causative factor in the development of cardiovascular disease as well. Atherosclerosis is a widely known condition in which the immune system causes harm to the host. Classically defined as a disease that is initiated by alterations in cholesterol metabolism and the subendothelial retention of low-density lipoproteins (LDL),2 we now know that activation of both innate and adaptive immunity participate in atherogenesis.3 Advanced atherosclerotic plaques are characterized by highly inflammatory lesions that can both impede blood flow and precipitate thrombosis because of plaque rupture, leading ultimately to the clinical manifestations of atherosclerosis: myocardial infarction, and stroke. The progression of atherosclerosis in humans is associated with increased circulating levels of proinflammatory C-reactive protein, as well as increased white blood cell count.3,4 A considerable amount of evidence implicates the innate immune system in the progression of atherosclerosis.5 Recent studies suggest that polymorphonuclear neutrophils (PMNs) drive the accumulation of monocytes in atherosclerotic lesions in a manner dependent on PMN granule proteins, such as the cathelicidins (ie, cathelicidin-related antimicrobial peptide).6–9 Other comorbidities, such as hyperglycemia, also contribute to the mobilization of PMNs from the bone marrow during atherosclerosis progression.10 Interestingly, the PMN/lymphocyte ratio may have value in predicting future cardiovascular events over
the white blood cell count alone.11 Although the role of PMNs in atherogenesis is emerging, the roles of monocytes and macrophages continue to be clarified further. Monocytes are recruited to sites of arterial inflammation because of subendothelial retention of LDL and the production of monocyte chemoattractants, such as chemokine (C-C-motif) ligand-2, sphingosine-1-phosphate, and CCL20.3,12,13 Hypercholesterolemia is associated with increased peripheral blood monocytes (ie, monocytosis), which arise from the bone marrow and splenic reservoirs.10,14 In mice, hypercholesterolemia promotes selective expansion of monocytes that express high levels of surface glycoprotein, Ly6C, which may arise, in part, because of granulocyte-macrophage colony-stimulating factor and interleukin (IL)-3–dependent extramedullary hematopoiesis.3,15,16 In humans with atherosclerosis, CD14HiCD16– monocytes analogously increase and are of predictive value in the context of cardiovascular disease.17 Acute myocardial infarction also increases monocytosis and atherosclerosis burden, which may relate to the fact that humans with a prior myocardial infarction have an increased risk for future cardiovascular events.18 Arterial inflammation at sites of disturbed blood flow and LDL retention facilitates monocyte adhesion via increases in inflammatory signaling pathways (ie, nuclear factor-κB, c-Jun N-terminal kinase-1) and subsequent surface expression of endothelial adhesion molecules.19 Interestingly, microparticles shed from activated or apoptotic cells can perpetuate this process by transferring adhesion molecules to endothelial cells.20 Recent evidence indicates that loss of endogenous counter-regulatory signaling pathways, such as inhibitor of differentiation 3 and Kruppel-like factor 2, also contributes to enhanced vascular inflammation and increased endothelial adhesion of both monocytes and PMNs.21–24 On infiltrating the vessel wall, monocytes differentiate into macrophages and rapidly take-up oxidatively modified LDL,25 a process that transforms macrophages into foam cells. In the absence of cholesterol efflux to high-density lipoprotein, which
From the Institute of Molecular Cardiology (M.S.), Diabetes and Obesity Center (M.S.), and Department of Microbiology and Immunology (M.S.), University of Louisville, Louisville, KY; and Department of Medicine, Columbia University, New York, NY (G.F.). Correspondence to Matthew Spite, PhD, Institute of Molecular Cardiology, University of Louisville, Louisville, KY. E-mail [email protected] (Circ Res. 2013;113:e111-e114.) © 2013 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.113.302986
Downloaded from http://circres.ahajournals.org/ e111 at Universitaet Zuerich on June 8, 2014
e112 Circulation Research December 6, 2013 is mediated, in part, by ATP-binding cassette transporters A1 (ABCA1) and ABCG1, foam cell formation propagates. It has been shown recently that myeloid-specific deficiency of both ABCA1 and ABCG1 increases atherosclerosis, monocytosis, and neutrophilia in mice and ABCA1-mediated cholesterol efflux is perturbed by hypoxia in macrophages.26,27 In addition, cholesterol efflux by these transporters also regulates chemotaxis of macrophages by redistributing membrane cholesterol from the inner leaflet of the cell membrane to the outer leaflet.28 Interestingly, it has been reported recently that ABCA1 deficiency increases macrophage clearance of Listeria monocytogenes, highlighting that perhaps the host response to bacterial infection evolved in a manner that increases risk for the development of sterile inflammatory diseases, such as atherosclerosis.29 Foam cells are abundant in atherosclerotic lesions and assume an M1 phenotype that perpetuates inflammation. Recent studies indicate that in addition to positive regulators of M1 activation (eg, interferon-γ), loss of endogenous counter- regulatory pathways, such as the nuclear receptor Nur77, may allow for M1 conversion and enhanced atherosclerosis.30 Moreover, macrophage populations in atherosclerotic lesions are heterogeneous because alternatively activated (M2) macrophages (mannose receptor; MR+) are also present and localize to stable areas of the plaque.31 These MR+ macrophages, which are generated in response to Th2 cytokines IL-4 and IL13, contain smaller lipid droplets than MR– macrophages, have lower cholesterol handling, and have a higher phagocytosis capability, which may be related to high levels of prominent M2 gene, 15-lipoxygenase.31 Moreover, M2 macrophage gene arginase-1 is upregulated by liver X receptor-α and may be a feature of macrophages in regressing plaques.32 This phenotype is characteristic of macrophages during the late phases of wound repair and actively resolving acute inflammation. Complete resolution of inflammation requires blunting of inflammatory gene transcription and the clearance of apoptotic cells (ie, efferocytosis).33 Interestingly, altered clearance of apoptotic macrophages is thought to give rise to necrotic cores characteristic of advanced atherosclerosis and, in support of this view, it has been demonstrated recently that deficiency of receptors that mediate apoptotic cell uptake (eg, Mertk) increases apoptotic cell accumulation in both atherosclerotic lesions and in the heart during myocardial infarction.25,34,35 Other emerging protective roles of macrophages in atherosclerosis include the autophagic processes that quiesce excessive lesional oxidative damage, decrease necrotic core formation, and regulate the inflammasome.36,37 In contrast, decreasing endoplasmic reticulum stress-mediated apoptosis through CCAAT/enhancer binding protein homologous protein deficiency seems to reduce necrotic core formation and plaque growth.38 Plaque development encompasses several processes, including monocyte infiltration, macrophage phenotype, and the dynamics of the clearance of apoptotic cells. The importance of monocyte recruitment as a driver of lesion development is underscored by a large body of literature demonstrating that genetic deficiency of monocyte chemokines (ie, CCL2) or their receptors blunts atherosclerosis progression.39 Adding to this body of evidence, using a novel mouse model of apolipoprotein E complementation, it was reported recently that
suppression of monocyte recruitment is sufficient to promote plaque regression.40 In addition to recruitment, other studies indicate that macrophages can proliferate locally in atherosclerotic lesions, which is a previously unrecognized mechanism for macrophage expansion first characterized in the context of a Th2 immune response during parasitic infection.41,42 There is also evidence that macrophages can leave atherosclerotic plaques, which has been demonstrated largely in animal models of atherosclerosis regression using aortic transplants. In these studies, macrophage removal from plaques was mediated by chemokine receptor, CCR7.39 Interestingly, CCR7dependent macrophage efflux from lesions may also underlie the atheroprotective effects of statins beyond lowering cholesterol.43 This view also suggests that a failure of macrophages to leave plaques may contribute to lesion progression, which is supported by a recent study demonstrating that neuroimmune guidance cue, netrin-1, retains macrophages in plaques by inhibiting their migration.44 Pro-inflammatory processes driven by lesional macrophages propagate atherosclerosis and emerging evidence points to new atherogenic roles for IL-1β and IL-1α.45,46 In addition to innate immunity, accumulating evidence suggests that extensive cross-talk between the innate and adaptive arms of the immune system contributes to atherogenesis.9 Dendritic cells (DCs), which classically link innate and adaptive immune responses as the key antigen-presenting cells, have emerged as mediators of atherosclerosis. Although both positive and negative contributions of plasmacytoid DCs in atherosclerosis progression have been described,47,48 recent studies indicate that CCL17+ (thymus and activation-regulated chemokine) DCs accumulate in both human and mouse plaques and that they promote atherosclerosis by suppressing regulatory T cells (Treg).49 These studies are in line with others supporting a proatherogenic role of DCs, in which these antigen-presenting cells stimulate CD4+ T cells to secrete inflammatory mediators in the vessel wall that, in turn, drive plaque progression. In contrast, MyD88 signaling in CD11c+ DCs was found to be important in stimulating Treg.50 Furthermore, recent studies demonstrated that depletion of protective Foxp3+ Treg promotes lesion development and that IL-2 therapy reduces atherosclerosis by stimulating CD4+CD25+Foxp3+ Treg proliferation.51–53 Unlike Treg, other T-cell populations, such as CD4+ T (Th1) cells and Th17 cells, contribute to atherosclerosis progression by producing inflammatory cytokines that recruit and polarize macrophages to an inflammatory phenotype.3,54 The role of Th17 cells in atherosclerosis is evidenced by decreased lesion formation and macrophage recruitment to atherosclerotic lesions in mice with genetic deficiency in IL17 or its receptor, IL-17-receptor A.55 Interestingly, the antiinflammatory cytokine, IL-27, was found to restrain IL-17A production during atherosclerosis, because mice deficient in the IL-27 receptor develop more atherosclerosis and have increased IL-17A production.56 However, the role of Th17 cells in atherosclerosis remains controversial because a separate study suggests that IL-17A deficiency does not affect lesion burden.57 Advanced atherosclerotic lesions are characterized by necrotic cores, which arise from postapoptotic secondary necrosis of macrophages and other cells within the plaque.25 Along these lines, cytotoxic CD8+ T cells directly promote the
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
Fredman and Spite Immunity in Atherosclerosis e113 accumulation of apoptotic cells in atherosclerotic lesions.58 Importantly, adoptive transfer of CD8+ cells deficient in granzyme B or perforin have been found not to enhance lesion development and apoptotic cell accumulation, implicating these cells as important drivers of plaque necrosis.58 Finally, an important contribution of humoral immunity to atherosclerosis has been gaining attention. Building on observations that depletion of B cells by anti-CD20 antibodies confers protection in atherosclerosis,59 Kyaw et al60,61 recently reported that different B-cell populations (ie, B1a versus B2) have divergent effects on atherogenesis. Specifically, B1a cells protect against atherosclerosis development by producing IgM antibodies, whereas B2 cells promote atherosclerosis independent of antibody production.60,61 These studies add to our understanding of the role of adaptive immunity in atherosclerosis and expand on prior studies demonstrating that natural antibody production to neoself antigens such as modified LDL are atheroprotective.62 Together, recent findings have helped solidify the concept that atherosclerosis is a chronic inflammatory disease. Therapeutically targeting the inflammatory response to blunt atherosclerosis is an intriguing concept that is currently being explored clinically.3,63 However, significant challenges remain because most anti-inflammatory strategies precipitate immunosuppression and increase susceptibility to infection.64,65 Although this might be considered to be an acceptable consequence on a short-term basis and has been used effectively, atherosclerosis is a disease that develops slowly for decades; therefore, immunomodulatory rather than immunosuppressive strategies may be more successful.65 Along these lines, emerging evidence indicates that actively resolving inflammation is mediated by agonists that not only dampen inflammation but also promote apoptotic cell removal and bacterial containment by phagocytes.33 Whether more precise inflammation- resolving strategies such as these can be beneficial in the context of atherosclerosis remains to be determined.
Sources of Funding The authors acknowledge the generous support of National Institutes of Health grants HL106173 (M.S.), GM103492 (M.S.) and HL119587 (G.F.).
Disclosures None.
References 1. Mann DL. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res. 2011;108:1133–1145. 2. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15:551–561. 3. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity. 2013;38:1092–1104. 4. Ortega E, Gilabert R, Nuñez I, Cofán M, Sala-Vila A, de Groot E, Ros E. White blood cell count is associated with carotid and femoral atherosclerosis. Atherosclerosis. 2012;221:275–281. 5. Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339:161–166. 6. Döring Y, Drechsler M, Wantha S, Kemmerich K, Lievens D, Vijayan S, Gallo RL, Weber C, Soehnlein O. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res. 2012;110:1052–1056.
7. Wantha S, Alard JE, Megens RT, van der Does AM, Döring Y, Drechsler M, Pham CT, Wang MW, Wang JM, Gallo RL, von Hundelshausen P, Lindbom L, Hackeng T, Weber C, Soehnlein O. Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ Res. 2013;112:792–801. 8. Swirski FK, Robbins CS. Neutrophils usher monocytes into sites of inflammation. Circ Res. 2013;112:744–745. 9. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–815. 10. Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang LS, Schmidt AM, Orchard TJ, Fisher EA, Tall AR, Goldberg IJ. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17:695–708. 11. Arbel Y, Finkelstein A, Halkin A, Birati EY, Revivo M, Zuzut M, Shevach A, Berliner S, Herz I, Keren G, Banai S. Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography. Atherosclerosis. 2012;225:456–460. 12. Keul P, Lucke S, von Wnuck Lipinski K, Bode C, Gräler M, Heusch G, Levkau B. Sphingosine-1-phosphate receptor 3 promotes recruitment of monocyte/macrophages in inflammation and atherosclerosis. Circ Res. 2011;108:314–323. 13. Wan W, Lim JK, Lionakis MS, Rivollier A, McDermott DH, Kelsall BL, Farber JM, Murphy PM. Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice. Circ Res. 2011;109:374–381. 14. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007;117:195–205. 15. Robbins CS, Chudnovskiy A, Rauch PJ, et al. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation. 2012;125:364–374. 16. Iwata H, Manabe I, Nagai R. Lineage of bone marrow-derived cells in atherosclerosis. Circ Res. 2013;112:1634–1647. 17. Berg KE, Ljungcrantz I, Andersson L, Bryngelsson C, Hedblad B, Fredrikson GN, Nilsson J, Björkbacka H. Elevated CD14++CD16monocytes predict cardiovascular events. Circ Cardiovasc Genet. 2012;5:122–131. 18. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487:325–329. 19. Cuhlmann S, Van der Heiden K, Saliba D, Tremoleda JL, Khalil M, Zakkar M, Chaudhury H, Luong le A, Mason JC, Udalova I, Gsell W, Jones H, Haskard DO, Krams R, Evans PC. Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. Circ Res. 2011;108:950–959. 20. Rautou PE, Leroyer AS, Ramkhelawon B, Devue C, Duflaut D, Vion AC, Nalbone G, Castier Y, Leseche G, Lehoux S, Tedgui A, Boulanger CM. Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration. Circ Res. 2011;108:335–343. 21. Lipinski MJ, Campbell KA, Duong SQ, Welch TJ, Garmey JC, Doran AC, Skaflen MD, Oldham SN, Kelly KA, McNamara CA. Loss of Id3 increases VCAM-1 expression, macrophage accumulation, and atherogenesis in Ldlr-/- mice. Arterioscler Thromb Vasc Biol. 2012;32:2855–2861. 22. Lingrel JB, Pilcher-Roberts R, Basford JE, Manoharan P, Neumann J, Konaniah ES, Srinivasan R, Bogdanov VY, Hui DY. Myeloid-specific Krüppel-like factor 2 inactivation increases macrophage and neutrophil adhesion and promotes atherosclerosis. Circ Res. 2012;110:1294–1302. 23. Shaked I, Ley K. Protective role for myeloid specific KLF2 in atherosclerosis. Circ Res. 2012;110:1266. 24. Wang XQ, Nigro P, World C, Fujiwara K, Yan C, Berk BC. Thioredoxin interacting protein promotes endothelial cell inflammation in response to disturbed flow by increasing leukocyte adhesion and repressing Kruppellike factor 2. Circ Res. 2012;110:560–568. 25. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145:341–355. 26. Westerterp M, Murphy AJ, Wang M, et al. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ Res. 2013;112:1456–1465. 27. Parathath S, Mick SL, Feig JE, Joaquin V, Grauer L, Habiel DM, Gassmann M, Gardner LB, Fisher EA. Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism. Circ Res. 2011;109:1141–1152.
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
e114 Circulation Research December 6, 2013 28. Pagler TA, Wang M, Mondal M, Murphy AJ, Westerterp M, Moore KJ, Maxfield FR, Tall AR. Deletion of ABCA1 and ABCG1 impairs macrophage migration because of increased Rac1 signaling. Circ Res. 2011;108:194–200. 29. Zhu X, Westcott MM, Bi X, Liu M, Gowdy KM, Seo J, Cao Q, Gebre AK, Fessler MB, Hiltbold EM, Hitbold EM, Parks JS. Myeloid cell-specific ABCA1 deletion protects mice from bacterial infection. Circ Res. 2012;111:1398–1409. 30. Hanna RN, Shaked I, Hubbeling HG, Punt JA, Wu R, Herrley E, Zaugg C, Pei H, Geissmann F, Ley K, Hedrick CC. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ Res. 2012;110:416–427. 31. Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y, Derudas B, Mayi T, Bories G, Tailleux A, Haulon S, Zawadzki C, Jude B, Staels B. 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. 32. Pourcet B, Feig JE, Vengrenyuk Y, Hobbs AJ, Kepka-Lenhart D, Garabedian MJ, Morris SM Jr, Fisher EA, Pineda-Torra I. LXRα regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8. Circ Res. 2011;109:492–501. 33. Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res. 2010;107:1170–1184. 34. Thorp E, Cui D, Schrijvers DM, Kuriakose G, Tabas I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice. Arterioscler Thromb Vasc Biol. 2008;28:1421–1428. 35. Wan E, Yeap XY, Dehn S, et al. Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circ Res. 2013;113:1004–1012. 36. Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, Ting JP, Virgin HW, Kastan MB, Semenkovich CF. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 2012;15:534–544. 37. Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 2012;15:545–553. 38. Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metab. 2009;9:474–481. 39. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13:709–721. 40. Potteaux S, Gautier EL, Hutchison SB, van Rooijen N, Rader DJ, Thomas MJ, Sorci-Thomas MG, Randolph GJ. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. J Clin Invest. 2011;121:2025–2036. 41. Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013;19:1166–1172. 42. Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, MacDonald AS, Allen JE. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011;332:1284–1288. 43. Feig JE, Shang Y, Rotllan N, Vengrenyuk Y, Wu C, Shamir R, Torra IP, Fernandez-Hernando C, Fisher EA, Garabedian MJ. Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. PLoS One. 2011;6:e28534. 44. van Gils JM, Derby MC, Fernandes LR, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol. 2012;13:136–143. 45. Sheedy FJ, Grebe A, Rayner KJ, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14:812–820. 46. Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, Hersberger M, Kopf M. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1 alpha and sterile vascular inflammation in atherosclerosis. Nat Immunol. 2013;14:1045–1053.
47. Daissormont IT, Christ A, Temmerman L, et al. Plasmacytoid dendritic cells protect against atherosclerosis by tuning T-cell proliferation and activity. Circ Res. 2011;109:1387–1395. 48. Macritchie N, Grassia G, Sabir SR, Maddaluno M, Welsh P, Sattar N, Ialenti A, Kurowska-Stolarska M, McInnes IB, Brewer JM, Garside P, Maffia P. Plasmacytoid dendritic cells play a key role in promoting atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2012;32:2569–2579. 49. Weber C, Meiler S, Döring Y, et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011;121:2898–2910. 50. Subramanian M, Thorp E, Hansson GK, Tabas I. Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest. 2013;123:179–188. 51. Klingenberg R, Gerdes N, Badeau RM, Gistera A, Strodthoff D, Ketelhuth DF, Lundberg AM, Rudling M, Nilsson SK, Olivecrona G, Zoller S, Lohmann C, Luscher TF, Jauhiainen M, Sparwasser T, Hansson GK. Depletion of foxp3+ regulatory t cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest. 2013;123:1323–1334. 52. Dietrich T, Hucko T, Schneemann C, Neumann M, Menrad A, Willuda J, Atrott K, Stibenz D, Fleck E, Graf K, Menssen HD. Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells. Atherosclerosis. 2012;220:329–336. 53. Dinh TN, Kyaw TS, Kanellakis P, To K, Tipping P, Toh BH, Bobik A, Agrotis A. Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation. 2012;126:1256–1266. 54. Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res. 2012;110:889–900. 55. Butcher MJ, Gjurich BN, Phillips T, Galkina EV. The IL-17A/IL-17RA axis plays a proatherogenic role via the regulation of aortic myeloid cell recruitment. Circ Res. 2012;110:675–687. 56. Koltsova EK, Kim G, Lloyd KM, Saris CJ, von Vietinghoff S, Kronenberg M, Ley K. Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice. Circ Res. 2012;111:1274–1285. 57. Madhur MS, Funt SA, Li L, Vinh A, Chen W, Lob HE, Iwakura Y, Blinder Y, Rahman A, Quyyumi AA, Harrison DG. Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein edeficient mice. Arterioscler Thromb Vasc Biol. 2011;31:1565–1572. 58. Kyaw T, Winship A, Tay C, Kanellakis P, Hosseini H, Cao A, Li P, Tipping P, Bobik A, Toh BH. Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in apoEdeficient mice. Circulation. 2013;127:1028–1039. 59. Ait-Oufella H, Herbin O, Bouaziz JD, Binder CJ, Uyttenhove C, Laurans L, Taleb S, Van Vré E, Esposito B, Vilar J, Sirvent J, Van Snick J, Tedgui A, Tedder TF, Mallat Z. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med. 2010;207:1579–1587. 60. Kyaw T, Tay C, Hosseini H, Kanellakis P, Gadowski T, MacKay F, Tipping P, Bobik A, Toh BH. Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. PLoS One. 2012;7:e29371. 61. Kyaw T, Tay C, Krishnamurthi S, Kanellakis P, Agrotis A, Tipping P, Bobik A, Toh BH. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ Res. 2011;109:830–840. 62. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res. 2011;108:235–248. 63. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317–325. 64. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871–882. 65. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science. 2013;339:166–172.
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/113/12/e111
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
Recent Developments Recent Developments in Cardiovascular Research: The goal of Recent Developments is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and impact of work performed in other fields. It is our hope and expectation that these Recent Developments articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research. — The Editors
Recent Advances in the Role of Immunity in Atherosclerosis Gabrielle Fredman, Matthew Spite
T
he immune system serves to protect the host from a diverse array of pathogens that evolve rapidly in an effort to breach immune security checkpoints. These defense mechanisms operate continuously to keep exogenous pathogens from propagating their own species, although this heightened security has unintended and detrimental consequences to the host.1 Although this maladaptive immune response is classically associated with noninfectious diseases, such as arthritis, gout, and lupus, uncontrolled inflammation is emerging as a causative factor in the development of cardiovascular disease as well. Atherosclerosis is a widely known condition in which the immune system causes harm to the host. Classically defined as a disease that is initiated by alterations in cholesterol metabolism and the subendothelial retention of low-density lipoproteins (LDL),2 we now know that activation of both innate and adaptive immunity participate in atherogenesis.3 Advanced atherosclerotic plaques are characterized by highly inflammatory lesions that can both impede blood flow and precipitate thrombosis because of plaque rupture, leading ultimately to the clinical manifestations of atherosclerosis: myocardial infarction, and stroke. The progression of atherosclerosis in humans is associated with increased circulating levels of proinflammatory C-reactive protein, as well as increased white blood cell count.3,4 A considerable amount of evidence implicates the innate immune system in the progression of atherosclerosis.5 Recent studies suggest that polymorphonuclear neutrophils (PMNs) drive the accumulation of monocytes in atherosclerotic lesions in a manner dependent on PMN granule proteins, such as the cathelicidins (ie, cathelicidin-related antimicrobial peptide).6–9 Other comorbidities, such as hyperglycemia, also contribute to the mobilization of PMNs from the bone marrow during atherosclerosis progression.10 Interestingly, the PMN/lymphocyte ratio may have value in predicting future cardiovascular events over
the white blood cell count alone.11 Although the role of PMNs in atherogenesis is emerging, the roles of monocytes and macrophages continue to be clarified further. Monocytes are recruited to sites of arterial inflammation because of subendothelial retention of LDL and the production of monocyte chemoattractants, such as chemokine (C-C-motif) ligand-2, sphingosine-1-phosphate, and CCL20.3,12,13 Hypercholesterolemia is associated with increased peripheral blood monocytes (ie, monocytosis), which arise from the bone marrow and splenic reservoirs.10,14 In mice, hypercholesterolemia promotes selective expansion of monocytes that express high levels of surface glycoprotein, Ly6C, which may arise, in part, because of granulocyte-macrophage colony-stimulating factor and interleukin (IL)-3–dependent extramedullary hematopoiesis.3,15,16 In humans with atherosclerosis, CD14HiCD16– monocytes analogously increase and are of predictive value in the context of cardiovascular disease.17 Acute myocardial infarction also increases monocytosis and atherosclerosis burden, which may relate to the fact that humans with a prior myocardial infarction have an increased risk for future cardiovascular events.18 Arterial inflammation at sites of disturbed blood flow and LDL retention facilitates monocyte adhesion via increases in inflammatory signaling pathways (ie, nuclear factor-κB, c-Jun N-terminal kinase-1) and subsequent surface expression of endothelial adhesion molecules.19 Interestingly, microparticles shed from activated or apoptotic cells can perpetuate this process by transferring adhesion molecules to endothelial cells.20 Recent evidence indicates that loss of endogenous counter-regulatory signaling pathways, such as inhibitor of differentiation 3 and Kruppel-like factor 2, also contributes to enhanced vascular inflammation and increased endothelial adhesion of both monocytes and PMNs.21–24 On infiltrating the vessel wall, monocytes differentiate into macrophages and rapidly take-up oxidatively modified LDL,25 a process that transforms macrophages into foam cells. In the absence of cholesterol efflux to high-density lipoprotein, which
From the Institute of Molecular Cardiology (M.S.), Diabetes and Obesity Center (M.S.), and Department of Microbiology and Immunology (M.S.), University of Louisville, Louisville, KY; and Department of Medicine, Columbia University, New York, NY (G.F.). Correspondence to Matthew Spite, PhD, Institute of Molecular Cardiology, University of Louisville, Louisville, KY. E-mail [email protected] (Circ Res. 2013;113:e111-e114.) © 2013 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.113.302986
Downloaded from http://circres.ahajournals.org/ e111 at Universitaet Zuerich on June 8, 2014
e112 Circulation Research December 6, 2013 is mediated, in part, by ATP-binding cassette transporters A1 (ABCA1) and ABCG1, foam cell formation propagates. It has been shown recently that myeloid-specific deficiency of both ABCA1 and ABCG1 increases atherosclerosis, monocytosis, and neutrophilia in mice and ABCA1-mediated cholesterol efflux is perturbed by hypoxia in macrophages.26,27 In addition, cholesterol efflux by these transporters also regulates chemotaxis of macrophages by redistributing membrane cholesterol from the inner leaflet of the cell membrane to the outer leaflet.28 Interestingly, it has been reported recently that ABCA1 deficiency increases macrophage clearance of Listeria monocytogenes, highlighting that perhaps the host response to bacterial infection evolved in a manner that increases risk for the development of sterile inflammatory diseases, such as atherosclerosis.29 Foam cells are abundant in atherosclerotic lesions and assume an M1 phenotype that perpetuates inflammation. Recent studies indicate that in addition to positive regulators of M1 activation (eg, interferon-γ), loss of endogenous counter- regulatory pathways, such as the nuclear receptor Nur77, may allow for M1 conversion and enhanced atherosclerosis.30 Moreover, macrophage populations in atherosclerotic lesions are heterogeneous because alternatively activated (M2) macrophages (mannose receptor; MR+) are also present and localize to stable areas of the plaque.31 These MR+ macrophages, which are generated in response to Th2 cytokines IL-4 and IL13, contain smaller lipid droplets than MR– macrophages, have lower cholesterol handling, and have a higher phagocytosis capability, which may be related to high levels of prominent M2 gene, 15-lipoxygenase.31 Moreover, M2 macrophage gene arginase-1 is upregulated by liver X receptor-α and may be a feature of macrophages in regressing plaques.32 This phenotype is characteristic of macrophages during the late phases of wound repair and actively resolving acute inflammation. Complete resolution of inflammation requires blunting of inflammatory gene transcription and the clearance of apoptotic cells (ie, efferocytosis).33 Interestingly, altered clearance of apoptotic macrophages is thought to give rise to necrotic cores characteristic of advanced atherosclerosis and, in support of this view, it has been demonstrated recently that deficiency of receptors that mediate apoptotic cell uptake (eg, Mertk) increases apoptotic cell accumulation in both atherosclerotic lesions and in the heart during myocardial infarction.25,34,35 Other emerging protective roles of macrophages in atherosclerosis include the autophagic processes that quiesce excessive lesional oxidative damage, decrease necrotic core formation, and regulate the inflammasome.36,37 In contrast, decreasing endoplasmic reticulum stress-mediated apoptosis through CCAAT/enhancer binding protein homologous protein deficiency seems to reduce necrotic core formation and plaque growth.38 Plaque development encompasses several processes, including monocyte infiltration, macrophage phenotype, and the dynamics of the clearance of apoptotic cells. The importance of monocyte recruitment as a driver of lesion development is underscored by a large body of literature demonstrating that genetic deficiency of monocyte chemokines (ie, CCL2) or their receptors blunts atherosclerosis progression.39 Adding to this body of evidence, using a novel mouse model of apolipoprotein E complementation, it was reported recently that
suppression of monocyte recruitment is sufficient to promote plaque regression.40 In addition to recruitment, other studies indicate that macrophages can proliferate locally in atherosclerotic lesions, which is a previously unrecognized mechanism for macrophage expansion first characterized in the context of a Th2 immune response during parasitic infection.41,42 There is also evidence that macrophages can leave atherosclerotic plaques, which has been demonstrated largely in animal models of atherosclerosis regression using aortic transplants. In these studies, macrophage removal from plaques was mediated by chemokine receptor, CCR7.39 Interestingly, CCR7dependent macrophage efflux from lesions may also underlie the atheroprotective effects of statins beyond lowering cholesterol.43 This view also suggests that a failure of macrophages to leave plaques may contribute to lesion progression, which is supported by a recent study demonstrating that neuroimmune guidance cue, netrin-1, retains macrophages in plaques by inhibiting their migration.44 Pro-inflammatory processes driven by lesional macrophages propagate atherosclerosis and emerging evidence points to new atherogenic roles for IL-1β and IL-1α.45,46 In addition to innate immunity, accumulating evidence suggests that extensive cross-talk between the innate and adaptive arms of the immune system contributes to atherogenesis.9 Dendritic cells (DCs), which classically link innate and adaptive immune responses as the key antigen-presenting cells, have emerged as mediators of atherosclerosis. Although both positive and negative contributions of plasmacytoid DCs in atherosclerosis progression have been described,47,48 recent studies indicate that CCL17+ (thymus and activation-regulated chemokine) DCs accumulate in both human and mouse plaques and that they promote atherosclerosis by suppressing regulatory T cells (Treg).49 These studies are in line with others supporting a proatherogenic role of DCs, in which these antigen-presenting cells stimulate CD4+ T cells to secrete inflammatory mediators in the vessel wall that, in turn, drive plaque progression. In contrast, MyD88 signaling in CD11c+ DCs was found to be important in stimulating Treg.50 Furthermore, recent studies demonstrated that depletion of protective Foxp3+ Treg promotes lesion development and that IL-2 therapy reduces atherosclerosis by stimulating CD4+CD25+Foxp3+ Treg proliferation.51–53 Unlike Treg, other T-cell populations, such as CD4+ T (Th1) cells and Th17 cells, contribute to atherosclerosis progression by producing inflammatory cytokines that recruit and polarize macrophages to an inflammatory phenotype.3,54 The role of Th17 cells in atherosclerosis is evidenced by decreased lesion formation and macrophage recruitment to atherosclerotic lesions in mice with genetic deficiency in IL17 or its receptor, IL-17-receptor A.55 Interestingly, the antiinflammatory cytokine, IL-27, was found to restrain IL-17A production during atherosclerosis, because mice deficient in the IL-27 receptor develop more atherosclerosis and have increased IL-17A production.56 However, the role of Th17 cells in atherosclerosis remains controversial because a separate study suggests that IL-17A deficiency does not affect lesion burden.57 Advanced atherosclerotic lesions are characterized by necrotic cores, which arise from postapoptotic secondary necrosis of macrophages and other cells within the plaque.25 Along these lines, cytotoxic CD8+ T cells directly promote the
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
Fredman and Spite Immunity in Atherosclerosis e113 accumulation of apoptotic cells in atherosclerotic lesions.58 Importantly, adoptive transfer of CD8+ cells deficient in granzyme B or perforin have been found not to enhance lesion development and apoptotic cell accumulation, implicating these cells as important drivers of plaque necrosis.58 Finally, an important contribution of humoral immunity to atherosclerosis has been gaining attention. Building on observations that depletion of B cells by anti-CD20 antibodies confers protection in atherosclerosis,59 Kyaw et al60,61 recently reported that different B-cell populations (ie, B1a versus B2) have divergent effects on atherogenesis. Specifically, B1a cells protect against atherosclerosis development by producing IgM antibodies, whereas B2 cells promote atherosclerosis independent of antibody production.60,61 These studies add to our understanding of the role of adaptive immunity in atherosclerosis and expand on prior studies demonstrating that natural antibody production to neoself antigens such as modified LDL are atheroprotective.62 Together, recent findings have helped solidify the concept that atherosclerosis is a chronic inflammatory disease. Therapeutically targeting the inflammatory response to blunt atherosclerosis is an intriguing concept that is currently being explored clinically.3,63 However, significant challenges remain because most anti-inflammatory strategies precipitate immunosuppression and increase susceptibility to infection.64,65 Although this might be considered to be an acceptable consequence on a short-term basis and has been used effectively, atherosclerosis is a disease that develops slowly for decades; therefore, immunomodulatory rather than immunosuppressive strategies may be more successful.65 Along these lines, emerging evidence indicates that actively resolving inflammation is mediated by agonists that not only dampen inflammation but also promote apoptotic cell removal and bacterial containment by phagocytes.33 Whether more precise inflammation- resolving strategies such as these can be beneficial in the context of atherosclerosis remains to be determined.
Sources of Funding The authors acknowledge the generous support of National Institutes of Health grants HL106173 (M.S.), GM103492 (M.S.) and HL119587 (G.F.).
Disclosures None.
References 1. Mann DL. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res. 2011;108:1133–1145. 2. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15:551–561. 3. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity. 2013;38:1092–1104. 4. Ortega E, Gilabert R, Nuñez I, Cofán M, Sala-Vila A, de Groot E, Ros E. White blood cell count is associated with carotid and femoral atherosclerosis. Atherosclerosis. 2012;221:275–281. 5. Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339:161–166. 6. Döring Y, Drechsler M, Wantha S, Kemmerich K, Lievens D, Vijayan S, Gallo RL, Weber C, Soehnlein O. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res. 2012;110:1052–1056.
7. Wantha S, Alard JE, Megens RT, van der Does AM, Döring Y, Drechsler M, Pham CT, Wang MW, Wang JM, Gallo RL, von Hundelshausen P, Lindbom L, Hackeng T, Weber C, Soehnlein O. Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ Res. 2013;112:792–801. 8. Swirski FK, Robbins CS. Neutrophils usher monocytes into sites of inflammation. Circ Res. 2013;112:744–745. 9. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–815. 10. Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang LS, Schmidt AM, Orchard TJ, Fisher EA, Tall AR, Goldberg IJ. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17:695–708. 11. Arbel Y, Finkelstein A, Halkin A, Birati EY, Revivo M, Zuzut M, Shevach A, Berliner S, Herz I, Keren G, Banai S. Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography. Atherosclerosis. 2012;225:456–460. 12. Keul P, Lucke S, von Wnuck Lipinski K, Bode C, Gräler M, Heusch G, Levkau B. Sphingosine-1-phosphate receptor 3 promotes recruitment of monocyte/macrophages in inflammation and atherosclerosis. Circ Res. 2011;108:314–323. 13. Wan W, Lim JK, Lionakis MS, Rivollier A, McDermott DH, Kelsall BL, Farber JM, Murphy PM. Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice. Circ Res. 2011;109:374–381. 14. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007;117:195–205. 15. Robbins CS, Chudnovskiy A, Rauch PJ, et al. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation. 2012;125:364–374. 16. Iwata H, Manabe I, Nagai R. Lineage of bone marrow-derived cells in atherosclerosis. Circ Res. 2013;112:1634–1647. 17. Berg KE, Ljungcrantz I, Andersson L, Bryngelsson C, Hedblad B, Fredrikson GN, Nilsson J, Björkbacka H. Elevated CD14++CD16monocytes predict cardiovascular events. Circ Cardiovasc Genet. 2012;5:122–131. 18. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487:325–329. 19. Cuhlmann S, Van der Heiden K, Saliba D, Tremoleda JL, Khalil M, Zakkar M, Chaudhury H, Luong le A, Mason JC, Udalova I, Gsell W, Jones H, Haskard DO, Krams R, Evans PC. Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. Circ Res. 2011;108:950–959. 20. Rautou PE, Leroyer AS, Ramkhelawon B, Devue C, Duflaut D, Vion AC, Nalbone G, Castier Y, Leseche G, Lehoux S, Tedgui A, Boulanger CM. Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration. Circ Res. 2011;108:335–343. 21. Lipinski MJ, Campbell KA, Duong SQ, Welch TJ, Garmey JC, Doran AC, Skaflen MD, Oldham SN, Kelly KA, McNamara CA. Loss of Id3 increases VCAM-1 expression, macrophage accumulation, and atherogenesis in Ldlr-/- mice. Arterioscler Thromb Vasc Biol. 2012;32:2855–2861. 22. Lingrel JB, Pilcher-Roberts R, Basford JE, Manoharan P, Neumann J, Konaniah ES, Srinivasan R, Bogdanov VY, Hui DY. Myeloid-specific Krüppel-like factor 2 inactivation increases macrophage and neutrophil adhesion and promotes atherosclerosis. Circ Res. 2012;110:1294–1302. 23. Shaked I, Ley K. Protective role for myeloid specific KLF2 in atherosclerosis. Circ Res. 2012;110:1266. 24. Wang XQ, Nigro P, World C, Fujiwara K, Yan C, Berk BC. Thioredoxin interacting protein promotes endothelial cell inflammation in response to disturbed flow by increasing leukocyte adhesion and repressing Kruppellike factor 2. Circ Res. 2012;110:560–568. 25. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145:341–355. 26. Westerterp M, Murphy AJ, Wang M, et al. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ Res. 2013;112:1456–1465. 27. Parathath S, Mick SL, Feig JE, Joaquin V, Grauer L, Habiel DM, Gassmann M, Gardner LB, Fisher EA. Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism. Circ Res. 2011;109:1141–1152.
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
e114 Circulation Research December 6, 2013 28. Pagler TA, Wang M, Mondal M, Murphy AJ, Westerterp M, Moore KJ, Maxfield FR, Tall AR. Deletion of ABCA1 and ABCG1 impairs macrophage migration because of increased Rac1 signaling. Circ Res. 2011;108:194–200. 29. Zhu X, Westcott MM, Bi X, Liu M, Gowdy KM, Seo J, Cao Q, Gebre AK, Fessler MB, Hiltbold EM, Hitbold EM, Parks JS. Myeloid cell-specific ABCA1 deletion protects mice from bacterial infection. Circ Res. 2012;111:1398–1409. 30. Hanna RN, Shaked I, Hubbeling HG, Punt JA, Wu R, Herrley E, Zaugg C, Pei H, Geissmann F, Ley K, Hedrick CC. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ Res. 2012;110:416–427. 31. Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y, Derudas B, Mayi T, Bories G, Tailleux A, Haulon S, Zawadzki C, Jude B, Staels B. 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. 32. Pourcet B, Feig JE, Vengrenyuk Y, Hobbs AJ, Kepka-Lenhart D, Garabedian MJ, Morris SM Jr, Fisher EA, Pineda-Torra I. LXRα regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8. Circ Res. 2011;109:492–501. 33. Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res. 2010;107:1170–1184. 34. Thorp E, Cui D, Schrijvers DM, Kuriakose G, Tabas I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice. Arterioscler Thromb Vasc Biol. 2008;28:1421–1428. 35. Wan E, Yeap XY, Dehn S, et al. Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circ Res. 2013;113:1004–1012. 36. Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, Ting JP, Virgin HW, Kastan MB, Semenkovich CF. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 2012;15:534–544. 37. Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 2012;15:545–553. 38. Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metab. 2009;9:474–481. 39. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13:709–721. 40. Potteaux S, Gautier EL, Hutchison SB, van Rooijen N, Rader DJ, Thomas MJ, Sorci-Thomas MG, Randolph GJ. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. J Clin Invest. 2011;121:2025–2036. 41. Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013;19:1166–1172. 42. Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, MacDonald AS, Allen JE. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011;332:1284–1288. 43. Feig JE, Shang Y, Rotllan N, Vengrenyuk Y, Wu C, Shamir R, Torra IP, Fernandez-Hernando C, Fisher EA, Garabedian MJ. Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. PLoS One. 2011;6:e28534. 44. van Gils JM, Derby MC, Fernandes LR, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol. 2012;13:136–143. 45. Sheedy FJ, Grebe A, Rayner KJ, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14:812–820. 46. Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, Hersberger M, Kopf M. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1 alpha and sterile vascular inflammation in atherosclerosis. Nat Immunol. 2013;14:1045–1053.
47. Daissormont IT, Christ A, Temmerman L, et al. Plasmacytoid dendritic cells protect against atherosclerosis by tuning T-cell proliferation and activity. Circ Res. 2011;109:1387–1395. 48. Macritchie N, Grassia G, Sabir SR, Maddaluno M, Welsh P, Sattar N, Ialenti A, Kurowska-Stolarska M, McInnes IB, Brewer JM, Garside P, Maffia P. Plasmacytoid dendritic cells play a key role in promoting atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2012;32:2569–2579. 49. Weber C, Meiler S, Döring Y, et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011;121:2898–2910. 50. Subramanian M, Thorp E, Hansson GK, Tabas I. Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest. 2013;123:179–188. 51. Klingenberg R, Gerdes N, Badeau RM, Gistera A, Strodthoff D, Ketelhuth DF, Lundberg AM, Rudling M, Nilsson SK, Olivecrona G, Zoller S, Lohmann C, Luscher TF, Jauhiainen M, Sparwasser T, Hansson GK. Depletion of foxp3+ regulatory t cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest. 2013;123:1323–1334. 52. Dietrich T, Hucko T, Schneemann C, Neumann M, Menrad A, Willuda J, Atrott K, Stibenz D, Fleck E, Graf K, Menssen HD. Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells. Atherosclerosis. 2012;220:329–336. 53. Dinh TN, Kyaw TS, Kanellakis P, To K, Tipping P, Toh BH, Bobik A, Agrotis A. Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation. 2012;126:1256–1266. 54. Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res. 2012;110:889–900. 55. Butcher MJ, Gjurich BN, Phillips T, Galkina EV. The IL-17A/IL-17RA axis plays a proatherogenic role via the regulation of aortic myeloid cell recruitment. Circ Res. 2012;110:675–687. 56. Koltsova EK, Kim G, Lloyd KM, Saris CJ, von Vietinghoff S, Kronenberg M, Ley K. Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice. Circ Res. 2012;111:1274–1285. 57. Madhur MS, Funt SA, Li L, Vinh A, Chen W, Lob HE, Iwakura Y, Blinder Y, Rahman A, Quyyumi AA, Harrison DG. Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein edeficient mice. Arterioscler Thromb Vasc Biol. 2011;31:1565–1572. 58. Kyaw T, Winship A, Tay C, Kanellakis P, Hosseini H, Cao A, Li P, Tipping P, Bobik A, Toh BH. Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in apoEdeficient mice. Circulation. 2013;127:1028–1039. 59. Ait-Oufella H, Herbin O, Bouaziz JD, Binder CJ, Uyttenhove C, Laurans L, Taleb S, Van Vré E, Esposito B, Vilar J, Sirvent J, Van Snick J, Tedgui A, Tedder TF, Mallat Z. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med. 2010;207:1579–1587. 60. Kyaw T, Tay C, Hosseini H, Kanellakis P, Gadowski T, MacKay F, Tipping P, Bobik A, Toh BH. Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. PLoS One. 2012;7:e29371. 61. Kyaw T, Tay C, Krishnamurthi S, Kanellakis P, Agrotis A, Tipping P, Bobik A, Toh BH. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ Res. 2011;109:830–840. 62. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res. 2011;108:235–248. 63. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317–325. 64. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871–882. 65. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science. 2013;339:166–172.
Downloaded from http://circres.ahajournals.org/ at Universitaet Zuerich on June 8, 2014
