IMMUNE NETWORK

  • 제20권3호
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  • Pages.22.1-22.21
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  • 2020
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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DOI QR코드

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Deciphering Macrophage Phenotypes upon Lipid Uptake and Atherosclerosis

  • Jihye Lee (Department of Life Science, College of Natural Sciences, Research Institute of Natural Sciences, Hanyang University) ;
  • Jae-Hoon Choi (Department of Life Science, College of Natural Sciences, Research Institute of Natural Sciences, Hanyang University)
  • 투고 : 2020.03.24
  • 심사 : 2020.06.15
  • 발행 : 2020.06.30
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초록

In the progression of atherosclerosis, macrophages are the key immune cells for foam cell formation. During hyperlipidemic condition, phagocytic cells such as monocytes and macrophages uptake oxidized low-density lipoproteins (oxLDLs) accumulated in subintimal space, and lipid droplets are accumulated in their cytosols. In this review, we discussed the characteristics and phenotypic changes of macrophages in atherosclerosis and the effect of cytosolic lipid accumulation on macrophage phenotype. Due to macrophage plasticity, the inflammatory phenotypes triggered by oxLDL can be re-programmed by cytosolic lipid accumulation, showing downregulation of NF-κB activation followed by activation of anti-inflammatory genes, leading to tissue repair and homeostasis. We also discuss about various in vivo and in vitro models for atherosclerosis research and next generation sequencing technologies for foam cell gene expression profiling. Analysis of the phenotypic changes of macrophages during the progression of atherosclerosis with adequate approach may lead to exact understandings of the cellular mechanisms and hint therapeutic targets for the treatment of atherosclerosis.

키워드

과제정보

This research was supported by the research grants (NRF-2016M3A9D5A01952413, 2018R1A2B6003393 and 2015M3A9B6029138) supported by the National Research Foundation of Korea.

참고문헌

  1. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003;3:23-35. https://doi.org/10.1038/nri978
  2. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 2012;13:1118-1128. https://doi.org/10.1038/ni.2419
  3. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT, Sahebkar A. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018;233:6425-6440. https://doi.org/10.1002/jcp.26429
  4. Medzhitov R. Origin and physiological roles of inflammation. Nature 2008;454:428-435. https://doi.org/10.1038/nature07201
  5. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 2016;44:450-462. https://doi.org/10.1016/j.immuni.2016.02.015
  6. Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity 2014;41:694-707. https://doi.org/10.1016/j.immuni.2014.10.008
  7. Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity 2014;41:21-35. https://doi.org/10.1016/j.immuni.2014.06.013
  8. Davies LC, Taylor PR. Tissue-resident macrophages: then and now. Immunology 2015;144:541-548. https://doi.org/10.1111/imm.12451
  9. Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, Brija T, Gautier EL, Ivanov S, Satpathy AT, et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 2014;40:91-104. https://doi.org/10.1016/j.immuni.2013.11.019
  10. Jones CV, Ricardo SD. Macrophages and CSF-1: implications for development and beyond. Organogenesis 2013;9:249-260. https://doi.org/10.4161/org.25676
  11. Tabas I, Lichtman AH. Monocyte-macrophages and t cells in atherosclerosis. Immunity 2017;47:621-634. https://doi.org/10.1016/j.immuni.2017.09.008
  12. Davies LC, Rosas M, Jenkins SJ, Liao CT, Scurr MJ, Brombacher F, Fraser DJ, Allen JE, Jones SA, Taylor PR. Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat Commun 2013;4:1886.
  13. Bajpai G, Bredemeyer A, Li W, Zaitsev K, Koenig AL, Lokshina I, Mohan J, Ivey B, Hsiao HM, Weinheimer C, et al. Tissue resident ccr2- and ccr2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ Res 2019;124:263-278. https://doi.org/10.1161/CIRCRESAHA.118.314028
  14. Liddiard K, Rosas M, Davies LC, Jones SA, Taylor PR. Macrophage heterogeneity and acute inflammation. Eur J Immunol 2011;41:2503-2508. https://doi.org/10.1002/eji.201141743
  15. Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011;11:738-749. https://doi.org/10.1038/nri3071
  16. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197-216. https://doi.org/10.1146/annurev.immunol.20.083001.084359
  17. Serhan CN. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not? Am J Pathol 2010;177:1576-1591. https://doi.org/10.2353/ajpath.2010.100322
  18. Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol 2014;5:614.
  19. Stienstra R, Duval C, Keshtkar S, van der Laak J, Kersten S, Muller M. Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J Biol Chem 2008;283:22620-22627. https://doi.org/10.1074/jbc.M710314200
  20. Kurowska-Stolarska M, Stolarski B, Kewin P, Murphy G, Corrigan CJ, Ying S, Pitman N, Mirchandani A, Rana B, van Rooijen N, et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol 2009;183:6469-6477. https://doi.org/10.4049/jimmunol.0901575
  21. Lech M, Anders HJ. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta 2013;1832:989-997. https://doi.org/10.1016/j.bbadis.2012.12.001
  22. Patel U, Rajasingh S, Samanta S, Cao T, Dawn B, Rajasingh J. Macrophage polarization in response to epigenetic modifiers during infection and inflammation. Drug Discov Today 2017;22:186-193. https://doi.org/10.1016/j.drudis.2016.08.006
  23. Fujiu K, Wang J, Nagai R. Cardioprotective function of cardiac macrophages. Cardiovasc Res 2014;102:232-239. https://doi.org/10.1093/cvr/cvu059
  24. Lin SL, Castano AP, Nowlin BT, Lupher ML Jr, Duffield JS. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol 2009;183:6733-6743. https://doi.org/10.4049/jimmunol.0901473
  25. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, Jung S, Amit I. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 2014;159:1312-1326. https://doi.org/10.1016/j.cell.2014.11.018
  26. Atri C, Guerfali FZ, Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci 2018;19:19.
  27. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006;6:508-519. https://doi.org/10.1038/nri1882
  28. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014;114:1852-1866. https://doi.org/10.1161/CIRCRESAHA.114.302721
  29. Gerrity RG, Naito HK, Richardson M, Schwartz CJ. Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages. Am J Pathol 1979;95:775-792.
  30. Xu H, Jiang J, Chen W, Li W, Chen Z. Vascular macrophages in atherosclerosis. J Immunol Res 2019;2019:4354786.
  31. Mestas J, Ley K. Monocyte-endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc Med 2008;18:228-232. https://doi.org/10.1016/j.tcm.2008.11.004
  32. Combadiere C, Potteaux S, Rodero M, Simon T, Pezard A, Esposito B, Merval R, Proudfoot A, Tedgui A, Mallat Z. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 2008;117:1649-1657. https://doi.org/10.1161/CIRCULATIONAHA.107.745091
  33. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007;117:185-194. https://doi.org/10.1172/JCI28549
  34. Goossens P, Gijbels MJ, Zernecke A, Eijgelaar W, Vergouwe MN, van der Made I, Vanderlocht J, Beckers L, Buurman WA, Daemen MJ, et al. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab 2010;12:142-153. https://doi.org/10.1016/j.cmet.2010.06.008
  35. Gerrity RG. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol 1981;103:181-190. 
  36. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011;145:341-355. https://doi.org/10.1016/j.cell.2011.04.005
  37. Ketelhuth DF, Hansson GK. Modulation of autoimmunity and atherosclerosis - common targets and promising translational approaches against disease. Circ J 2015;79:924-933. https://doi.org/10.1253/circj.CJ-15-0167
  38. Ketelhuth DF, Hansson GK. Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thromb Haemost 2011;106:779-786. https://doi.org/10.1160/TH11-05-0321
  39. Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019;124:315-327. https://doi.org/10.1161/CIRCRESAHA.118.313591
  40. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36-44. https://doi.org/10.1161/01.CIR.89.1.36
  41. Gerrity RG, Naito HK. Lipid clearance from fatty streak lesions by foam cell migration. Artery 1980;8:215-219. 
  42. Barrett TJ. Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol 2020;40:20-33. https://doi.org/10.1161/ATVBAHA.119.312802
  43. Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci U S A 2004;101:11779-11784. https://doi.org/10.1073/pnas.0403259101
  44. Boyle JJ, Harrington HA, Piper E, Elderfield K, Stark J, Landis RC, Haskard DO. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 2009;174:1097-1108. https://doi.org/10.2353/ajpath.2009.080431
  45. Boyle JJ. Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage. Curr Opin Lipidol 2012;23:453-461. https://doi.org/10.1097/MOL.0b013e328356b145
  46. Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, Elliott MR, Gruber F, Han J, Chen W, et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res 2010;107:737-746. https://doi.org/10.1161/CIRCRESAHA.109.215715
  47. Gleissner CA, Shaked I, Little KM, Ley K. CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol 2010;184:4810-4818. https://doi.org/10.4049/jimmunol.0901368
  48. Erbel C, Tyka M, Helmes CM, Akhavanpoor M, Rupp G, Domschke G, Linden F, Wolf A, Doesch A, Lasitschka F, et al. CXCL4-induced plaque macrophages can be specifically identified by co-expression of MMP7+S100A8+ in vitro and in vivo. Innate Immun 2015;21:255-265. https://doi.org/10.1177/1753425914526461
  49. Gleissner CA, Shaked I, Erbel C, Bockler D, Katus HA, Ley K. CXCL4 downregulates the atheroprotective hemoglobin receptor CD163 in human macrophages. Circ Res 2010;106:203-211. https://doi.org/10.1161/CIRCRESAHA.109.199505
  50. Chistiakov DA, Grechko AV, Myasoedova VA, Melnichenko AA, Orekhov AN. The role of monocytosis and neutrophilia in atherosclerosis. J Cell Mol Med 2018;22:1366-1382. https://doi.org/10.1111/jcmm.13462
  51. van Gils JM, Ramkhelawon B, Fernandes L, Stewart MC, Guo L, Seibert T, Menezes GB, Cara DC, Chow C, Kinane TB, et al. Endothelial expression of guidance cues in vessel wall homeostasis dysregulation under proatherosclerotic conditions. Arterioscler Thromb Vasc Biol 2013;33:911-919. https://doi.org/10.1161/ATVBAHA.112.301155
  52. van Gils JM, Derby MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, Parathath S, Distel E, Feig JL, Alvarez-Leite JI, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol 2012;13:136-143. https://doi.org/10.1038/ni.2205
  53. Wanschel A, Seibert T, Hewing B, Ramkhelawon B, Ray TD, van Gils JM, Rayner KJ, Feig JE, O'Brien ER, Fisher EA, et al. Neuroimmune guidance cue Semaphorin 3E is expressed in atherosclerotic plaques and regulates macrophage retention. Arterioscler Thromb Vasc Biol 2013;33:886-893. https://doi.org/10.1161/ATVBAHA.112.300941
  54. Qian YN, Luo YT, Duan HX, Feng LQ, Bi Q, Wang YJ, Yan XY. Adhesion molecule CD146 and its soluble form correlate well with carotid atherosclerosis and plaque instability. CNS Neurosci Ther 2014;20:438-445. https://doi.org/10.1111/cns.12234
  55. Luo Y, Duan H, Qian Y, Feng L, Wu Z, Wang F, Feng J, Yang D, Qin Z, Yan X. Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. Cell Res 2017;27:352-372. https://doi.org/10.1038/cr.2017.8
  56. Moore KJ, Koplev S, Fisher EA, Tabas I, Bjorkegren JL, Doran AC, Kovacic JC. Macrophage trafficking, inflammatory resolution, and genomics in atherosclerosis: JACC macrophage in CVD series (part 2). J Am Coll Cardiol 2018;72:2181-2197. https://doi.org/10.1016/j.jacc.2018.08.2147
  57. 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.
  58. Wu C, Hussein MA, Shrestha E, Leone S, Aiyegbo MS, Lambert WM, Pourcet B, Cardozo T, Gustafson JA, Fisher EA, et al. Modulation of macrophage gene expression via liver x receptor alpha serine 198 phosphorylation. Mol Cell Biol 2015;35:2024-2034. https://doi.org/10.1128/MCB.00985-14
  59. Gage MC, Becares N, Louie R, Waddington KE, Zhang Y, Tittanegro TH, Rodriguez-Lorenzo S, Jathanna A, Pourcet B, Pello OM, et al. Disrupting LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation. Proc Natl Acad Sci U S A 2018;115:E6556-E6565. https://doi.org/10.1073/pnas.1721245115
  60. Feig JE, Vengrenyuk Y, Reiser V, Wu C, Statnikov A, Aliferis CF, Garabedian MJ, Fisher EA, Puig O. Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome. PLoS One 2012;7:e39790.
  61. Wang Y, Dubland JA, Allahverdian S, Asonye E, Sahin B, Jaw JE, Sin DD, Seidman MA, Leeper NJ, Francis GA. Smooth muscle cells contribute the majority of foam cells in apoe (apolipoprotein e)-deficient mouse atherosclerosis. Arterioscler Thromb Vasc Biol 2019;39:876-887. https://doi.org/10.1161/ATVBAHA.119.312434
  62. Kim K, Shim D, Lee JS, Zaitsev K, Williams JW, Kim KW, Jang MY, Seok Jang H, Yun TJ, Lee SH, et al. Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ Res 2018;123:1127-1142. https://doi.org/10.1161/CIRCRESAHA.118.312804
  63. Cochain C, Zernecke A. Macrophages in vascular inflammation and atherosclerosis. Pflugers Arch 2017;469:485-499. https://doi.org/10.1007/s00424-017-1941-y
  64. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M, Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T, et al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 1997;386:292-296. https://doi.org/10.1038/386292a0
  65. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013;13:709-721. https://doi.org/10.1038/nri3520
  66. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34-47. https://doi.org/10.1126/science.3513311
  67. de Winther MP, van Dijk KW, Havekes LM, Hofker MH. Macrophage scavenger receptor class A: a multifunctional receptor in atherosclerosis. Arterioscler Thromb Vasc Biol 2000;20:290-297. https://doi.org/10.1161/01.ATV.20.2.290
  68. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 1993;268:11811-11816. https://doi.org/10.1016/S0021-9258(19)50272-1
  69. Murphy JE, Tedbury PR, Homer-Vanniasinkam S, Walker JH, Ponnambalam S. Biochemistry and cell biology of mammalian scavenger receptors. Atherosclerosis 2005;182:1-15. https://doi.org/10.1016/j.atherosclerosis.2005.03.036
  70. Acton SL, Scherer PE, Lodish HF, Krieger M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J Biol Chem 1994;269:21003-21009. https://doi.org/10.1016/S0021-9258(17)31921-X
  71. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996;271:518-520. https://doi.org/10.1126/science.271.5248.518
  72. Brown AJ, Mander EL, Gelissen IC, Kritharides L, Dean RT, Jessup W. Cholesterol and oxysterol metabolism and subcellular distribution in macrophage foam cells. Accumulation of oxidized esters in lysosomes. J Lipid Res 2000;41:226-237. https://doi.org/10.1016/S0022-2275(20)32056-3
  73. Ouimet M, Franklin V, Mak E, Liao X, Tabas I, Marcel YL. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab 2011;13:655-667. https://doi.org/10.1016/j.cmet.2011.03.023
  74. Viaud M, Ivanov S, Vujic N, Duta-Mare M, Aira LE, Barouillet T, Garcia E, Orange F, Dugail I, Hainault I, et al. Lysosomal cholesterol hydrolysis couples efferocytosis to anti-inflammatory oxysterol production. Circ Res 2018;122:1369-1384. https://doi.org/10.1161/CIRCRESAHA.117.312333
  75. Chang TY, Chang CC, Cheng D. Acyl-coenzyme A:cholesterol acyltransferase. Annu Rev Biochem 1997;66:613-638. https://doi.org/10.1146/annurev.biochem.66.1.613
  76. de Winther MP, Hofker MH. Scavenging new insights into atherogenesis. J Clin Invest 2000;105:1039-1041. https://doi.org/10.1172/JCI9919
  77. Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell 2001;104:503-516. https://doi.org/10.1016/S0092-8674(01)00238-0
  78. Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol 2015;15:104-116. https://doi.org/10.1038/nri3793
  79. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010;11:155-161. https://doi.org/10.1038/ni.1836
  80. Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, 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. https://doi.org/10.1038/ni.2639
  81. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357-1361. https://doi.org/10.1038/nature08938
  82. Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS, Flavell RA. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995;267:2000-2003. https://doi.org/10.1126/science.7535475
  83. Randolph GJ. Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res 2014;114:1757-1771. https://doi.org/10.1161/CIRCRESAHA.114.301174
  84. Sikorski K, Chmielewski S, Olejnik A, Wesoly JZ, Heemann U, Baumann M, Bluyssen H. STAT1 as a central mediator of IFNγ and TLR4 signal integration in vascular dysfunction. JAK-STAT 2012;1:241-249. https://doi.org/10.4161/jkst.22469
  85. Chen Y, Yang M, Huang W, Chen W, Zhao Y, Schulte ML, Volberding P, Gerbec Z, Zimmermann MT, Zeighami A, et al. Mitochondrial metabolic reprogramming by cd36 signaling drives macrophage inflammatory responses. Circ Res 2019;125:1087-1102. https://doi.org/10.1161/CIRCRESAHA.119.315833
  86. Dennis EA, Deems RA, Harkewicz R, Quehenberger O, Brown HA, Milne SB, Myers DS, Glass CK, Hardiman G, Reichart D, et al. A mouse macrophage lipidome. J Biol Chem 2010;285:39976-39985. https://doi.org/10.1074/jbc.M110.182915
  87. Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, Reichart D, Fox JN, Shaked I, Heudobler D, et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 2012;151:138-152. https://doi.org/10.1016/j.cell.2012.06.054
  88. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010;142:687-698.
  89. Rios FJ, Koga MM, Pecenin M, Ferracini M, Gidlund M, Jancar S. Oxidized LDL induces alternative macrophage phenotype through activation of CD36 and PAFR. Mediators Inflamm 2013;2013:198193.
  90. Butcher MJ, Galkina EV. Phenotypic and functional heterogeneity of macrophages and dendritic cell subsets in the healthy and atherosclerosis-prone aorta. Front Physiol 2012;3:44.
  91. Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell 2006;124:35-46. https://doi.org/10.1016/j.cell.2005.12.022
  92. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002;109:1125-1131. https://doi.org/10.1172/JCI0215593
  93. Bennett MK, Lopez JM, Sanchez HB, Osborne TF. Sterol regulation of fatty acid synthase promoter. Coordinate feedback regulation of two major lipid pathways. J Biol Chem 1995;270:25578-25583. https://doi.org/10.1074/jbc.270.43.25578
  94. Ericsson J, Jackson SM, Kim JB, Spiegelman BM, Edwards PA. Identification of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor 1- and sterol regulatory element-binding protein-responsive gene. J Biol Chem 1997;272:7298-7305. https://doi.org/10.1074/jbc.272.11.7298
  95. Lounis MA, Bergeron KF, Burhans MS, Ntambi JM, Mounier C. Oleate activates SREBP-1 signaling activity in SCD1-deficient hepatocytes. Am J Physiol Endocrinol Metab 2017;313:E710-E720. https://doi.org/10.1152/ajpendo.00151.2017
  96. Moon YA, Shah NA, Mohapatra S, Warrington JA, Horton JD. Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J Biol Chem 2001;276:45358-45366. https://doi.org/10.1074/jbc.M108413200
  97. Im SS, Yousef L, Blaschitz C, Liu JZ, Edwards RA, Young SG, Raffatellu M, Osborne TF. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 2011;13:540-549. https://doi.org/10.1016/j.cmet.2011.04.001
  98. Oishi Y, Spann NJ, Link VM, Muse ED, Strid T, Edillor C, Kolar MJ, Matsuzaka T, Hayakawa S, Tao J, et al. Srebp1 contributes to resolution of pro-inflammatory tlr4 signaling by reprogramming fatty acid metabolism. Cell Metab 2017;25:412-427. https://doi.org/10.1016/j.cmet.2016.11.009
  99. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, et al. Role of LXRs in control of lipogenesis. Genes Dev 2000;14:2831-2838.  https://doi.org/10.1101/gad.850400
  100. Jongstra-Bilen J, Zhang CX, Wisnicki T, Li MK, White-Alfred S, Ilaalagan R, Ferri DM, Deonarain A, Wan MH, Hyduk SJ, et al. Oxidized low-density lipoprotein loading of macrophages downregulates tlr-induced proinflammatory responses in a gene-specific and temporal manner through transcriptional control. J Immunol 2017;199:2149-2157. https://doi.org/10.4049/jimmunol.1601363
  101. Ito A, Hong C, Rong X, Zhu X, Tarling EJ, Hedde PN, Gratton E, Parks J, Tontonoz P. LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. eLife 2015;4:e08009.
  102. Baardman J, Verberk SGS, Prange KHM, van Weeghel M, van der Velden S, Ryan DG, Wust RCI, Neele AE, Speijer D, Denis SW, et al. A defective pentose phosphate pathway reduces inflammatory macrophage responses during hypercholesterolemia. Cell Rep 2018;25:2044-2052.e2045. https://doi.org/10.1016/j.celrep.2018.10.092
  103. Emini Veseli B, Perrotta P, De Meyer GR, Roth L, Van der Donckt C, Martinet W, De Meyer GR. Animal models of atherosclerosis. Eur J Pharmacol 2017;816:3-13. https://doi.org/10.1016/j.ejphar.2017.05.010
  104. Getz GS, Reardon CA. Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32:1104-1115. https://doi.org/10.1161/ATVBAHA.111.237693
  105. Meir KS, Leitersdorf E. Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress. Arterioscler Thromb Vasc Biol 2004;24:1006-1014. https://doi.org/10.1161/01.ATV.0000128849.12617.f4
  106. Piedrahita JA, Zhang SH, Hagaman JR, Oliver PM, Maeda N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A 1992;89:4471-4475. https://doi.org/10.1073/pnas.89.10.4471
  107. Silvestre-Roig C, de Winther MP, Weber C, Daemen MJ, Lutgens E, Soehnlein O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circ Res 2014;114:214-226. https://doi.org/10.1161/CIRCRESAHA.114.302355
  108. Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 1994;93:1885-1893. https://doi.org/10.1172/JCI117179
  109. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A 2004;101:7100-7105. https://doi.org/10.1073/pnas.0402133101
  110. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A 2005;102:5374-5379. https://doi.org/10.1073/pnas.0501652102
  111. Roche-Molina M, Sanz-Rosa D, Cruz FM, Garcia-Prieto J, Lopez S, Abia R, Muriana FJ, Fuster V, Ibanez B, Bernal JA. Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9. Arterioscler Thromb Vasc Biol 2015;35:50-59. https://doi.org/10.1161/ATVBAHA.114.303617
  112. Goettsch C, Hutcheson JD, Hagita S, Rogers MA, Creager MD, Pham T, Choi J, Mlynarchik AK, Pieper B, Kjolby M, et al. A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification. Atherosclerosis 2016;251:109-118. https://doi.org/10.1016/j.atherosclerosis.2016.06.011
  113. Vozenilek AE, Blackburn CM, Schilke RM, Chandran S, Castore R, Klein RL, Woolard MD. AAV8-mediated overexpression of mPCSK9 in liver differs between male and female mice. Atherosclerosis 2018;278:66-72. https://doi.org/10.1016/j.atherosclerosis.2018.09.005
  114. Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 1987;68:231-240. https://doi.org/10.1016/0021-9150(87)90202-4
  115. Ji R, Li X, Zhou C, Tian Q, Li C, Xia S, Wang R, Feng Y, Zhan W. Identifying macrophage enrichment in atherosclerotic plaques by targeting dual-modal US imaging/MRI based on biodegradable Fe-doped hollow silica nanospheres conjugated with anti-CD68 antibody. Nanoscale 2018;10:20246-20255. https://doi.org/10.1039/C8NR04703K
  116. Lougheed M, Lum CM, Ling W, Suzuki H, Kodama T, Steinbrecher U. High affinity saturable uptake of oxidized low density lipoprotein by macrophages from mice lacking the scavenger receptor class A type I/ II. J Biol Chem 1997;272:12938-12944.  https://doi.org/10.1074/jbc.272.20.12938
  117. Feig JE, Fisher EA. Laser capture microdissection for analysis of macrophage gene expression from atherosclerotic lesions. Methods Mol Biol 2013;1027:123-135. https://doi.org/10.1007/978-1-60327-369-5_5
  118. Thomas AC, Eijgelaar WJ, Daemen MJ, Newby AC. Foam cell formation in vivo converts macrophages to a pro-fibrotic phenotype. PLoS One 2015;10:e0128163.
  119. de Gaetano M, Crean D, Barry M, Belton O. M1- and m2-type macrophage responses are predictive of adverse outcomes in human atherosclerosis. Front Immunol 2016;7:275.
  120. Jin X, Kruth HS. Culture of macrophage colony-stimulating factor differentiated human monocytederived macrophages. J Vis Exp 2016:54244.
  121. MacDonald C. Development of new cell lines for animal cell biotechnology. Crit Rev Biotechnol 1990;10:155-178. https://doi.org/10.3109/07388559009068265
  122. Kaur G, Dufour JM. Cell lines: valuable tools or useless artifacts. Spermatogenesis 2012;2:1-5. https://doi.org/10.4161/spmg.19885
  123. Makinen PI, Lappalainen JP, Heinonen SE, Leppanen P, Lahteenvuo MT, Aarnio JV, Heikkila J, Turunen MP, Yla-Herttuala S. Silencing of either SR-A or CD36 reduces atherosclerosis in hyperlipidaemic mice and reveals reciprocal upregulation of these receptors. Cardiovasc Res 2010;88:530-538. https://doi.org/10.1093/cvr/cvq235
  124. Qin Z. The use of THP-1 cells as a model for mimicking the function and regulation of monocytes and macrophages in the vasculature. Atherosclerosis 2012;221:2-11. https://doi.org/10.1016/j.atherosclerosis.2011.09.003
  125. Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno T, Tada K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer 1980;26:171-176. https://doi.org/10.1002/ijc.2910260208
  126. Zhao YL, Tian PX, Han F, Zheng J, Xia XX, Xue WJ, Ding XM, Ding CG. Comparison of the characteristics of macrophages derived from murine spleen, peritoneal cavity, and bone marrow. J Zhejiang Univ Sci B 2017;18:1055-1063. https://doi.org/10.1631/jzus.B1700003
  127. Trouplin V, Boucherit N, Gorvel L, Conti F, Mottola G, Ghigo E. Bone marrow-derived macrophage production. J Vis Exp 2013:e50966.
  128. Lavin Y, Merad M. Macrophages: gatekeepers of tissue integrity. Cancer Immunol Res 2013;1:201-209. https://doi.org/10.1158/2326-6066.CIR-13-0117
  129. Sohn M, Na HY, Ryu SH, Choi W, In H, Shin HS, Park JS, Shim D, Shin SJ, Park CG. Two distinct subsets are identified from the peritoneal myeloid mononuclear cells expressing both CD11c and CD115. Immune Netw 2019;19:e15.
  130. Ghosn EE, Cassado AA, Govoni GR, Fukuhara T, Yang Y, Monack DM, Bortoluci KR, Almeida SR, Herzenberg LA, Herzenberg LA. Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proc Natl Acad Sci U S A 2010;107:2568-2573. https://doi.org/10.1073/pnas.0915000107
  131. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 2013;38:79-91. https://doi.org/10.1016/j.immuni.2012.12.001
  132. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 2013;38:792-804. https://doi.org/10.1016/j.immuni.2013.04.004
  133. Morrisey EE, Ip HS, Lu MM, Parmacek MS. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev Biol 1996;177:309-322. https://doi.org/10.1006/dbio.1996.0165
  134. Leijh PC, van Zwet TL, ter Kuile MN, van Furth R. Effect of thioglycolate on phagocytic and microbicidal activities of peritoneal macrophages. Infect Immun 1984;46:448-452. https://doi.org/10.1128/iai.46.2.448-452.1984
  135. Meza-Perez S, Randall TD. Immunological functions of the omentum. Trends Immunol 2017;38:526-536.  https://doi.org/10.1016/j.it.2017.03.002
  136. Zhang N, Czepielewski RS, Jarjour NN, Erlich EC, Esaulova E, Saunders BT, Grover SP, Cleuren AC, Broze GJ, Edelson BT, et al. Expression of factor V by resident macrophages boosts host defense in the peritoneal cavity. J Exp Med 2019;216:1291-1300. https://doi.org/10.1084/jem.20182024
  137. Cassado AA, D'Imperio Lima MR, Bortoluci KR. Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. Front Immunol 2015;6:225.
  138. Winkels H, Ehinger E, Vassallo M, Buscher K, Dinh HQ, Kobiyama K, Hamers AA, Cochain C, Vafadarnejad E, Saliba AE, et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ Res 2018;122:1675-1688. https://doi.org/10.1161/CIRCRESAHA.117.312513
  139. Cochain C, Vafadarnejad E, Arampatzi P, Pelisek J, Winkels H, Ley K, Wolf D, Saliba AE, Zernecke A. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ Res 2018;122:1661-1674. https://doi.org/10.1161/CIRCRESAHA.117.312509
  140. Kim K, Choi JH. Response by Kim and Choi to letter regarding article, "Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models". Circ Res 2018;123:e50.