Macrophages are key integrators of inflammatory and metabolic signals in atherosclerotic plaques.
The macrophage content of the plaque and the activation state of the macrophages changes during both the progression and the regression of atherosclerosis.
The macrophage content of the plaque represents the kinetic balance between the recruitment of blood monocytes, their differentiation into tissue macrophages and proliferation in situ, and their emigration or death.
The lipid content of macrophages promotes innate immune responses and inflammation both by increasing the sensitivity of Toll-like receptors to their ligands and by activating the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome.
The study of new mouse models of atherosclerosis regression has established the reversibility of macrophage accumulation and activation in plaques, which challenges the long-held belief that failing to resolve chronic inflammation is an inevitable feature of atherosclerosis.
Atherosclerosis is a chronic inflammatory disease that arises from an imbalance in lipid metabolism and a maladaptive immune response driven by the accumulation of cholesterol-laden macrophages in the artery wall. Through the analysis of the progression and regression of atherosclerosis in animal models, there is a growing understanding that the balance of macrophages in the plaque is dynamic and that both macrophage numbers and the inflammatory phenotype influence plaque fate. In this Review, we summarize recently identified pro- and anti-inflammatory pathways that link lipid and inflammation biology with the retention of macrophages in plaques, as well as factors that have the potential to promote their egress from these sites.
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Moore, K. J. & Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341–355 (2011).
Randolph, G. J. Emigration of monocyte-derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis. Curr. Opin. Lipidol. 19, 462–468 (2008).
Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010).
Feig, J. E. et al. Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 123, 989–998 (2011). This study describes the use of Reversa mice as a model of atherosclerosis regression.
Feig, J. E. et al. HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc. Natl Acad. Sci. USA 108, 7166–7171 (2011).
Llodra, J. et al. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc. Natl Acad. Sci. USA 101, 11779–11784 (2004). This study shows the emigration of CD68+ cells from regressing atherosclerotic plaques.
Averill, L. E., Meagher, R. C. & Gerrity, R. G. Enhanced monocyte progenitor cell proliferation in bone marrow of hyperlipemic swine. Am. J. Pathol. 135, 369–377 (1989).
Feldman, D. L., Mogelesky, T. C., Liptak, B. F. & Gerrity, R. G. Leukocytosis in rabbits with diet-induced atherosclerosis. Arterioscler. Thromb. 11, 985–994 (1991).
Swirski, F. K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007). This study shows that Apoe−/− mice have a monocytosis that is due to an increase in the LY6Chi monocyte population.
Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007). This study shows that Apoe−/− mice have a monocytosis and it describes the chemokine receptors that contribute to monocyte recruitment in progressing plaques.
Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010). This study establishes the essential role of cellular cholesterol efflux in suppressing haematopoietic stem cell proliferation.
Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).
Tabas, I., Williams, K. J. & Boren, J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116, 1832–1844 (2007).
Glass, C. K. & Witztum, J. L. Atherosclerosis: the road ahead. Cell 104, 503–516 (2001).
Paulson, K. E. et al. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ. Res. 106, 383–390 (2010).
Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).
Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).
Soehnlein, O. et al. Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol. Med. 5, 471–481 (2013).
Woollard, K. J. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nature Rev. Cardiol. 7, 77–86 (2010).
Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nature Med. 17, 1410–1422 (2011).
Combadiere, C. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6Chi and Ly6Clo monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 117, 1649–1657 (2008).
Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunol. 7, 311–317 (2006).
Landsman, L. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113, 963–972 (2009).
van Gils, J. M. et al. Endothelial expression of guidance cues in vessel wall homeostasis dysregulation under proatherosclerotic conditions. Arterioscler. Thromb. Vasc. Biol. 33, 911–919 (2013). This study shows that neuronal guidance molecules are differentially expressed on the endothelium in athero-prone and athero-protected regions of the vasculature.
van Gils, J. M. et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nature Immunol. 13, 136–143 (2012). This work identifies netrin 1 as a retention signal that blocks macrophage egress from inflamed vessel walls in the presence of hypercholesterolaemia, which leads to chronic vessel wall inflammation and plaque progression.
Wanschel, A. et al. Neuroimmune guidance cue semaphorin 3E is expressed in atherosclerotic plaques and regulates macrophage retention. Arterioscler. Thromb. Vasc. Biol. 33, 886–893 (2013).
Moore, K. J. & Freeman, M. W. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler. Thromb. Vasc. Biol. 26, 1702–1711 (2006).
Miller, Y. I. et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ. Res. 108, 235–248 (2011).
Kunjathoor, V. V. et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem. 277, 49982–49988 (2002).
Podrez, E. A., Schmitt, D., Hoff, H. F. & Hazen, S. L. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J. Clin. Invest. 103, 1547–1560 (1999).
Kzhyshkowska, J., Neyen, C. & Gordon, S. Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 217, 492–502 (2012).
Maxfield, F. R. & Tabas, I. Role of cholesterol and lipid organization in disease. Nature 438, 612–621 (2005).
Kuchibhotla, S. et al. Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II. Cardiovasc. Res. 78, 185–196 (2008).
Manning-Tobin, J. J. et al. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler. Thromb. Vasc. Biol. 29, 19–26 (2009).
Tardif, J. C. Antioxidants: the good, the bad and the ugly. Can. J. Cardiol. 22 (Suppl. B), 61B–65B (2006).
Boyanovsky, B. B., van der Westhuyzen, D. R. & Webb, N. R. Group V secretory phospholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independent process that involves cellular proteoglycans. J. Biol. Chem. 280, 32746–32752 (2005).
Oorni, K. & Kovanen, P. T. Lipoprotein modification by secretory phospholipase A2 enzymes contributes to the initiation and progression of atherosclerosis. Curr. Opin. Lipidol. 20, 421–427 (2009).
Lind, L. et al. Circulating levels of secretory- and lipoprotein-associated phospholipase A2 activities: relation to atherosclerotic plaques and future all-cause mortality. Eur. Heart J. 33, 2946–2954 (2012).
Kugiyama, K. et al. Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease. Circulation 100, 1280–1284 (1999).
Kruth, H. S. Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles. Curr. Opin. Lipidol. 22, 386–393 (2011). This is a discussion of studies that establish that native LDL can contribute to foam cell formation through its uptake via macrophage fluid-phase pinocytosis.
Zhu, X. et al. Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol. J. Lipid Res. 51, 3196–3206 (2010). This study shows that cholesterol enrichment of lipid rafts promotes signalling via TLRs.
Mogilenko, D. A. et al. Endogenous apolipoprotein A-I stabilizes ATP-binding cassette transporter A1 and modulates Toll-like receptor 4 signaling in human macrophages. FASEB J. 26, 2019–2030 (2012).
Yvan-Charvet, L. et al. Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation 118, 1837–1847 (2008).
Jerome, W. G. Advanced atherosclerotic foam cell formation has features of an acquired lysosomal storage disorder. Rejuven. Res. 9, 245–255 (2006).
Feng, B. et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nature Cell Biol. 5, 781–792 (2003).
Tabas, I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler. Thromb. Vasc. Biol. 25, 2255–2264 (2005).
Yvan-Charvet, L., Wang, N. & Tall, A. R. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler. Thromb. Vasc. Biol. 30, 139–143 (2010).
Spann, N. J. et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151, 138–152 (2012).
Calkin, A. C. & Tontonoz, P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nature Rev. Mol. Cell Biol. 13, 213–224 (2012).
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009). This study was the first to show a role for autophagy in regulating lipid metabolism.
Ouimet, M. et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell. Metab. 13, 655–667 (2011). This study shows that autophagy regulates cholesterol efflux in macrophage foam cells.
Liao, X. et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell. Metab. 15, 545–553 (2012). This study uncovers a protective role for the autophagy process in atherosclerosis through the regulation of plaque necrosis.
Razani, B. et al. Autophagy links inflammasomes to atherosclerotic progression. Cell. Metab. 15, 534–544 (2012). This study shows a protective role for the autophagy process in atherosclerosis through the regulation of inflammasome activation.
Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunol. 12, 222–230 (2011).
Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268 (2008).
Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). This study describes a role for the NLRP3 inflammasome in atherogenesis, thereby uncovering a previously unappreciated role of cholesterol crystals as key early initiators of vascular inflammation.
Lim, R. S. et al. Identification of cholesterol crystals in plaques of atherosclerotic mice using hyperspectral CARS imaging. J. Lipid Res. 52, 2177–2186 (2011).
Gage, J., Hasu, M., Thabet, M. & Whitman, S. C. Caspase-1 deficiency decreases atherosclerosis in apolipoprotein E-null mice. Can. J. Cardiol. 28, 222–229 (2012).
Usui, F. et al. Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice. Biochem. Biophys. Res. Commun. 425, 162–168 (2012).
Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008).
Freigang, S. et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur. J. Immunol. 41, 2040–2051 (2011).
Menu, P. et al. Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis. 2, e137 (2011).
Sheedy, F. J. et al. CD36 coordinates activation of the NLRP3 inflammasome by facilitating the intracellular nucleation of soluble to particulate ligands in sterile inflammation. Nature Immunol. 14, 812–820 (2013).
Niemi, K. et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J. Immunol. 186, 6119–6128 (2011).
Michelsen, K. S. et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl Acad. Sci. USA 101, 10679–10684 (2004).
Mullick, A. E., Tobias, P. S. & Curtiss, L. K. Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest. 115, 3149–3156 (2005).
Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunol. 11, 155–161 (2010). This study identifies a new TLR heterodimer, TLR4–TLR6, that is triggered by oxidized LDL through CD36 and that promotes pro-inflammatory signalling in macrophages.
Ding, Y. et al. Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese low-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 32, 1596–1604 (2012).
Kim, T. W. et al. The critical role of IL-1 receptor-associated kinase 4-mediated NF-κB activation in modified low-density lipoprotein-induced inflammatory gene expression and atherosclerosis. J. Immunol. 186, 2871–2880 (2011).
Rekhter, M. et al. Genetic ablation of IRAK4 kinase activity inhibits vascular lesion formation. Biochem. Biophys. Res. Commun. 367, 642–648 (2008).
Lutgens, E. et al. Deficient CD40–TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J. Exp. Med. 207, 391–404 (2010).
Richards, M. R. et al. The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice. Innate Immun. 19, 20–29 (2013).
Bjorkbacka, H. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Med. 10, 416–421 (2004).
Bae, Y. S. et al. Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ. Res. 104, 210–218 (2009).
Seimon, T. A. et al. Atherogenic lipids and lipoproteins trigger CD36–TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell. Metab. 12, 467–482 (2010).
Zhu, X. et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J. Biol. Chem. 283, 22930–22941 (2008).
Adamson, S. & Leitinger, N. Phenotypic modulation of macrophages in response to plaque lipids. Curr. Opin. Lipidol. 22, 335–342 (2011).
Chinetti-Gbaguidi, G. et al. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ. Res. 108, 985–995 (2011).
Gallardo-Soler, A. et al. Arginase I induction by modified lipoproteins in macrophages: a peroxisome proliferator-activated receptor-γ/δ-mediated effect that links lipid metabolism and immunity. Mol. Endocrinol. 22, 1394–1402 (2008).
Kadl, A. et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ. Res. 107, 737–746 (2010). This study identifies a new macrophage phenotype, termed the Mox macrophage, that occurs in macrophages that have been exposed to atherogenic phospholipids.
Hansson, G. K. & Hermansson, A. The immune system in atherosclerosis. Nature Immunol. 12, 204–212 (2011).
Hanna, R. N. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C− monocytes. Nature Immunol. 12, 778–785 (2011). This study identifies an important role for NR4A1 in M2 macrophage polarization.
Hanna, R. N. et al. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ. Res. 110, 416–427 (2012). This study reports that the deletion of NR4A1 worsens atherosclerosis by increasing macrophage polarization to the M1 phenotype.
Hamers, A. A. et al. Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis. Circ. Res. 110, 428–438 (2012). This study reports that deletion of NR4A1 worsens atherosclerosis and inflammation.
Chao, L. C. et al. Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice. J. Lipid Res. 54, 806–815 (2013). In contrast to references 83 and 84, this study finds no role for NR4A1 in macrophage polarization or atherogenesis.
Liao, X. et al. Krüppel-like factor 4 regulates macrophage polarization. J. Clin. Invest. 121, 2736–2749 (2011). This study identifies a key role for the transcription factor KLF4 in directing M2 macrophage polarization.
Sharma, N. et al. Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE−/− mice — brief report. Arterioscler. Thromb. Vasc. Biol. 32, 2836–2838 (2012). This study shows that the deletion of KLF4 leads to enhanced atherosclerosis in both chow-fed and Western diet-fed Apoe−/− mice.
Cardilo-Reis, L. et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol. Med. 4, 1072–1086 (2012).
Rayner, K. J. et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J. Clin. Invest. 121, 2921–2931 (2011).
Khallou-Laschet, J. et al. Macrophage plasticity in experimental atherosclerosis. PLoS ONE 5, e8852 (2010).
Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).
Zhang, M. Z. et al. CSF-1 signaling mediates recovery from acute kidney injury. J. Clin. Invest. 122, 4519–4532 (2012).
Zhu, S. N., Chen, M., Jongstra-Bilen, J. & Cybulsky, M. I. GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. J. Exp. Med. 206, 2141–2149 (2009).
Gerrity, R. G. & Naito, H. K. Lipid clearance from fatty streak lesions by foam cell migration. Artery 8, 215–219 (1980).
Ramkhelawon, B. et al. Hypoxia induces netrin-1 and unc5b in atherosclerotic plaques: mechanism for macrophage retention and survival. Arterioscler Thromb. Vasc. Biol. 33, 1180–1188 (2013).
Parathath, S. et al. Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism. Circ. Res. 109, 1141–1152 (2011).
Feig, J. E. et al. Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome. PLoS ONE 7, e39790 (2012). Through transcriptome analysis of macrophages in progressing and regressing plaques, this work identifies the genetic signature of macrophages during the resolution of atherosclerotic inflammation.
Trogan, E. et al. Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice. Proc. Natl Acad. Sci. USA 99, 2234–2239 (2002).
Yvan-Charvet, L. et al. ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis. Circ. Res. 106, 1861–1869 (2010).
Potteaux, S. et al. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe−/− mice during disease regression. J. Clin. Invest. 121, 2025–2036 (2011). In this model of atherosclerosis regression, which was achieved through the reconstitution of Apoe−/− mice with APOE, the authors show that reduced monocyte recruitment and increased apoptotic turnover of macrophages are crucial components of atherosclerosis resolution.
Nagareddy, P. R. et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell. Metab. 17, 695–708 (2013).
Raffai, R. L. & Weisgraber, K. H. Hypomorphic apolipoprotein E mice: a new model of conditional gene repair to examine apolipoprotein E-mediated metabolism. J. Biol. Chem. 277, 11064–11068 (2002).
Reis, E. D. et al. Dramatic remodeling of advanced atherosclerotic plaques of the apolipoprotein E-deficient mouse in a novel transplantation model. J. Vasc. Surg. 34, 541–547 (2001).
Rong, J. X. et al. Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content. Circulation 104, 2447–2452 (2001). This study reports that atherosclerosis regression that is induced by increased HDL levels is characterized by decreasing macrophage content and increasing smooth muscle cell content.
Feig, J. E. et al. Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. PLoS ONE 6, e28534 (2011).
Frias, J. C., Ma, Y., Williams, K. J., Fayad, Z. A. & Fisher, E. A. Properties of a versatile nanoparticle platform contrast agent to image and characterize atherosclerotic plaques by magnetic resonance imaging. Nano Lett. 6, 2220–2224 (2006).
Leuschner, F. et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nature Biotech. 29, 1005–1010 (2011).
Pan, H. et al. Programmable nanoparticle functionalization for in vivo targeting. FASEB J. 27, 255–264 (2013).
Egawa, M. et al. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4. Immunity 38, 570–580 (2013).
Denney, L. et al. Activation of invariant NKT cells in early phase of experimental autoimmune encephalomyelitis results in differentiation of Ly6Chi inflammatory monocyte to M2 macrophages and improved outcome. J. Immunol. 189, 551–557 (2012).
Schrijvers, D. M., De Meyer, G. R. & Martinet, W. Autophagy in atherosclerosis: a potential drug target for plaque stabilization. Arterioscler. Thromb. Vasc. Biol. 31, 2787–2791 (2011).
Thorp, E., Cui, D., Schrijvers, D. M., 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. 28, 1421–1428 (2008).
Zizzo, G., Hilliard, B. A., Monestier, M. & Cohen, P. L. Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J. Immunol. 189, 3508–3520 (2012).
Plump, A. S. et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71, 343–353 (1992).
Zhang, S. H., Reddick, R. L., Piedrahita, J. A. & Maeda, N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258, 468–471 (1992).
Ishibashi, S. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. Clin. Invest. 92, 883–893 (1993).
Robbins, C. S. et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nature Med. http://dx.doi.org/10.1038/nm.3258 (2013).
The work carried out in the authors' laboratories related to this Review is supported by the US National Institutes of Health (grants R01 HL084312 and P01 HL098055 to E.A.F.; and grants R01 R01HL117334 and R01HL108182 to K.J.M.).
The authors declare no competing financial interests.
- Foam cells
Macrophages in the arterial wall that ingest oxidized low-density lipoprotein and assume a foamy appearance. These cells secrete various substances that are involved in plaque growth.
- Myocardial infarction
An episode of acute cardiac ischaemia that leads to death of heart muscle cells. It is usually caused by a thrombotic atherosclerotic plaque.
- Atherosclerosis regression
A decrease in atherosclerotic plaque size that is typically accompanied by a reduction in lipid levels, immune cells and inflammatory gene expression.
- Leukocyte adhesion cascade
The key steps that are involved in leukocyte adhesion to the endothelium. These include rolling (which is mediated by selectins), activation (which is mediated by chemokines) and arrest (which is mediated by integrins). Recent additional steps have been defined that include capture (also known as tethering), slow rolling, adhesion strengthening and spreading, intravascular crawling, and paracellular and transcellular transmigration.
- Firm adhesion
The interactions of rolling leukocytes with chemokines or lipid mediators, such as leukotriene B4, at the endothelial surface leads to the activation of leukocyte integrins — another family of adhesion molecules. After they are activated, integrins mediate the high-affinity adhesive interactions between leukocytes and endothelial cells, which results in the arrest and firm adhesion of rolling leukocytes.
- Pattern recognition receptors
(PRRs). Host receptors (such as Toll-like receptors) that can sense pathogen-associated or damage-associated molecular patterns and that can initiate signalling cascades (which involve activation of nuclear factor-κB) that lead to an innate immune response.
Also known as fluid-phase endocytosis. A process of engulfment of extracellular fluid and its solutes. It can be mediated by an actin-dependent mechanism that results in the engulfment of large volumes (macropinocytosis) or by other mechanisms that result in the engulfment of smaller volumes (micropinocytosis).
The process of macrophage clearance of apoptotic cells.
- ATP-binding cassette subfamily A member 1
(ABCA1). A member of a superfamily of proteins that transport various molecules across extracellular and intracellular membranes using the energy of ATP hydrolysis. Eukaryotic ABC genes are classified in seven families, from ABCA to ABCG, on the basis of gene organization and primary sequence homology. Functional characterization can be partly made by differential sensitivity to inhibitory drugs.
An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation, through fusion to secondary lysosomes.
- NLRP3 inflammasome
A molecular complex containing NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and the adaptor molecule ASC that controls the activity of caspase 1. Formation of this complex results in the cleavage of the highly pro-inflammatory cytokines pro-interleukin-1β (IL-1β) and pro-IL-18, thereby producing active IL-1β and IL-18.
- M1 macrophages
Macrophages that are activated by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ and that express, among others, inducible nitric oxide synthase and nitric oxide.
- M2 macrophages
Macrophages that are stimulated by interleukin-4 (IL-4) or IL-13 and that express arginase 1, the mannose receptor 1 (also known as CD206) and the IL-4 receptor α-chain.
A single-stranded RNA molecule of approximately 21–23 nucleotides in length that regulates the expression of other genes.
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Moore, K., Sheedy, F. & Fisher, E. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13, 709–721 (2013). https://doi.org/10.1038/nri3520
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