Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Efferocytosis in atherosclerosis

Nature Reviews Cardiology (2024)Cite this article

Subjects

Abstract

Cardiovascular disease is the leading cause of death worldwide, and it commonly results from atherosclerotic plaque progression. One of the increasingly recognized drivers of atherosclerosis is dysfunctional efferocytosis, a homeostatic mechanism responsible for the clearance of dead cells and the resolution of inflammation. In atherosclerosis, the capacity of phagocytes to participate in efferocytosis is hampered, leading to the accumulation of apoptotic and necrotic tissue within the plaque, which results in enlargement of the necrotic core, increased luminal stenosis and plaque inflammation, and predisposition to plaque rupture or erosion. In this Review, we describe the different forms of programmed cell death that can occur in the atherosclerotic plaque and highlight the efferocytic machinery that is normally implicated in cardiovascular physiology. We then discuss the mechanisms by which efferocytosis fails in atherosclerosis and other cardiovascular and cardiometabolic diseases, including myocardial infarction and diabetes mellitus, and discuss therapeutic approaches that might reverse this pathological process.

Key points

  • Efferocytosis is a highly regulated and immunologically silent process through which diseased and dying cells are engulfed by phagocytes for clearance.

  • Integration of multiple signalling pathways involving an array of ligands and receptors ultimately determines whether apoptotic cells are phagocytosed.

  • Efferocytosis is impaired in atherosclerotic cardiovascular disease, secondary to inherited genetic variation, necrotic cell death, local inflammation and competitive inhibition by oxidized LDL.

  • The mechanism of cell death influences the capacity of phagocytes to perform efferocytosis.

  • A promising therapeutic strategy for cardiovascular disease is targeting the CD47–SIRPα axis, which might help to attenuate atherosclerosis and cardiac fibrosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms of impaired efferocytosis in atherosclerosis.
Fig. 2: Timeline of important discoveries on efferocytosis and atherosclerotic cardiovascular disease.
Fig. 3: Mechanisms of programmed cell death.

Similar content being viewed by others

References

  1. Crisby, M. et al. Cell death in human atherosclerotic plaques involves both oncosis and apoptosis. Atherosclerosis 130, 17–27 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Neunteufl, T. et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129, 111–118 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Bennett, M. R. Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovasc. Res. 41, 361–368 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Kockx, M. M. & Herman, A. G. Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc. Res. 45, 736–746 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Wada, Y. et al. In vitro model of atherosclerosis using coculture of arterial wall cells and macrophage. Yonsei Med. J. 41, 740–755 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Lazar, M. A. Progress in cardiovascular biology: PPAR for the course. Nat. Med. 7, 23–24 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Bennett, M. R., Evan, G. I. & Schwartz, S. M. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J. Clin. Invest. 95, 2266–2274 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Agewall, S. Anticoagulation, atherosclerosis, and heart failure. Eur. Hear. J. Cardiovasc. Pharmacother. 3, 1–2 (2017).

    Article  Google Scholar 

  9. Bevan, G. H. & Solaru, K. T. W. Evidence-based medical management of peripheral artery disease. Arterioscler. Thromb. Vasc. Biol. 40, 541–553 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Sarmah, D. et al. The role of inflammasomes in atherosclerosis and stroke pathogenesis. Curr. Pharm. Des. 26, 4234–4245 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Koton, S. et al. Association of ischemic stroke incidence, severity, and recurrence with dementia in the atherosclerosis risk in communities cohort study. JAMA Neurol. 79, 271–280 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Libby, P., Ridker, P. M. & Hansson, G. K. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Vaduganathan, M., Mensah, G. A., Turco, J. V., Fuster, V. & Roth, G. A. The global burden of cardiovascular diseases and risk a compass for future health. J. Am. Coll. Cardiol. 80, 2361–2371 (2022).

    Article  PubMed  Google Scholar 

  14. Bozkurt, B. et al. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association. Circulation 134, e535–e578 (2016).

    Article  PubMed  Google Scholar 

  15. Dasagrandhi, D., Muthuswamy, A. & Swaminathan, J. K. Atherosclerosis: nexus of vascular dynamics and cellular cross talks. Mol. Cell Biochem. 477, 571–584 (2022).

    Article  CAS  PubMed  Google Scholar 

  16. Huang, C.-L. et al. Association of lower extremity arterial calcification with amputation and mortality in patients with symptomatic peripheral artery disease. PLoS ONE 9, e90201 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liu, J. et al. Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 25, 174–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Rochette, L. et al. Interplay between efferocytosis and atherosclerosis. Arch. Cardiovasc. Dis. 116, 474–484 (2023).

    Article  PubMed  Google Scholar 

  19. Savill, J. Recognition and phagocytosis of cells undergoing apoptosis. Br. Med. Bull. 53, 491–508 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Henson, P. M., Bratton, D. L. & Fadok, V. A. Apoptotic cell removal. Curr. Biol. 11, R795–R805 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Morioka, S., Maueröder, C. & Ravichandran, K. S. Living on the edge: efferocytosis at the interface of homeostasis and pathology. Immunity 50, 1149–1162 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lin, D. et al. Efferocytosis and its associated cytokines: a light on non-tumor and tumor diseases? Mol. Ther. - Oncolytics 17, 394–407 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Thorp, E. B. Mechanisms of failed apoptotic cell clearance by phagocyte subsets in cardiovascular disease. Apoptosis 15, 1124–1136 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gerlach, B. D. et al. Resolvin D1 promotes the targeting and clearance of necroptotic cells. Cell Death Differ. 27, 525–539 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Gerlach, B. D. et al. Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metab. 33, 2445–2463.e8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mehrotra, P. & Ravichandran, K. S. Drugging the efferocytosis process: concepts and opportunities. Nat. Rev. Drug. Discov. 21, 601–620 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cabrera, J. T. O. & Makino, A. Efferocytosis of vascular cells in cardiovascular disease. Pharmacol. Ther. 229, 107919 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Wang, Y. et al. Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade. Proc. Natl Acad. Sci. USA 117, 15818–15826 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sorokin, V. et al. Role of vascular smooth muscle cell plasticity and interactions in vessel wall inflammation. Front. Immunol. 11, 599415 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tauber, A. I. Metchnikoff and the phagocytosis theory. Nat. Rev. Mol. Cell Biol. 4, 897–901 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Fadok, V. A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207–2216 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Franc, N. C., Dimarcq, J.-L., Lagueux, M., Hoffmann, J. & Ezekowitz, R. A. B. Croquemort, a novel Drosophila hemocyte/macrophage receptor that recognizes apoptotic cells. Immunity 4, 431–443 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Abrams, J. M., White, K., Fessler, L. I. & Steller, H. Programmed cell death during Drosophila embryogenesis. Development 117, 29–43 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. White, K. et al. Genetic control of programmed cell death in Drosophila. Science 264, 677–683 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Ellis, R. E., Jacobson, D. M. & Horvitz, H. R. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 129, 79–94 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, X. & Yang, C. Programmed cell death and clearance of cell corpses in Caenorhabditis elegans. Cell. Mol. Life Sci. 73, 2221–2236 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Shi, J. et al. A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis. Nat. Commun. 13, 7929 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kamber, R. A. et al. Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis. Nature 597, 549–554 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Haney, M. S. et al. Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens. Nat. Genet. 7, 1716–1727 (2018).

    Article  Google Scholar 

  40. Tang, D., Chen, X., Kang, R. & Kroemer, G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 31, 107–125 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Lin, X. et al. Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis. Arch. Biochem. Biophys. 715, 109098 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Puylaert, P., Zurek, M., Rayner, K. J., Meyer, G. R. Y. D. & Martinet, W. Regulated necrosis in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 42, 1283–1306 (2022).

    Article  CAS  PubMed  Google Scholar 

  43. Bertheloot, D., Latz, E. & Franklin, B. S. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell. Mol. Immunol. 18, 1106–1121 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Vasudevan, S. O., Behl, B. & Rathinam, V. A. Pyroptosis-induced inflammation and tissue damage. Semin. Immunol. 69, 101781 (2023).

    Article  CAS  PubMed  Google Scholar 

  45. Berghe, T. V. et al. Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ. 17, 922–930 (2010).

    Article  Google Scholar 

  46. Kojima, Y., Weissman, I. L. & Leeper, N. J. The role of efferocytosis in atherosclerosis. Circulation 135, 476–489 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang, D. et al. The molecular mechanisms of cuproptosis and its relevance to cardiovascular disease. Biomed. Pharmacother. 163, 114830 (2023).

    Article  CAS  PubMed  Google Scholar 

  48. Kerr, J. F. R., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Robertson, L. E. et al. Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine. Blood 81, 143–150 (1993).

    Article  CAS  PubMed  Google Scholar 

  50. Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Bevers, E. M., Comfurius, P., Dekkers, D. W. C. & Zwaal, R. F. A. Lipid translocation across the plasma membrane of mammalian cells. Biochim. Biophys. Acta 1439, 317–330 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Roelofsen, B. Molecular architecture and dynamics of the plasma membrane lipid bilayer: the red blood cell as a model. Infection 19, S206–S209 (1991).

    Article  CAS  PubMed  Google Scholar 

  53. Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Souilhol, C. et al. Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes. Nat. Rev. Cardiol. 17, 52–63 (2020).

    Article  PubMed  Google Scholar 

  55. Kaw, K. et al. Smooth muscle α-actin missense variant promotes atherosclerosis through modulation of intracellular cholesterol in smooth muscle cells. Eur. Hear. J. 44, 2713–2726 (2023).

    Article  CAS  Google Scholar 

  56. Kattoor, A. J., Pothineni, N. V. K., Palagiri, D. & Mehta, J. L. Oxidative stress in atherosclerosis. Curr. Atheroscler. Rep. 19, 42 (2017).

    Article  PubMed  Google Scholar 

  57. Hartley, A., Haskard, D. & Khamis, R. Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis – novel insights and future directions in diagnosis and therapy. Trends Cardiovasc. Med. 29, 22–26 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  59. Moriya, J. Critical roles of inflammation in atherosclerosis. J. Cardiol. 73, 22–27 (2019).

    Article  PubMed  Google Scholar 

  60. Kolodgie, F. D. et al. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am. J. Pathol. 157, 1259–1268 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Thorp, E. et al. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe−/− and Ldlr−/− mice lacking CHOP. Cell Metab. 9, 474–481 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Thorp, E. et al. Brief report: increased apoptosis in advanced atherosclerotic lesions of Apoe−/− mice lacking macrophage Bcl-2. Arterioscler. Thromb. Vasc. Biol. 29, 169–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Arai, S. et al. A role for the apoptosis inhibitory factor AIM/Spα/Api6 in atherosclerosis development. Cell Metab. 1, 201–213 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Gautier, E. L. et al. Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage. Circulation 119, 1795–1804 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Wu, X. et al. Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death Dis. 9, 171 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Fidler, T. P. et al. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. Nature 592, 296–301 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Park, E. & Chung, S. W. ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation. Cell Death Dis. 10, 822 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Rogers, C. et al. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8, 14128 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brouckaert, G. et al. Phagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production. Mol. Biol. Cell 15, 1089–1100 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Crouser, E. D. et al. Monocyte activation by necrotic cells is promoted by mitochondrial proteins and formyl peptide receptors. Crit. Care Med. 37, 2000–2009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Freeman, S. A. & Grinstein, S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol. Rev. 262, 193–215 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Imai, T. et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91, 521–530 (1997).

    Article  CAS  PubMed  Google Scholar 

  75. Truman, L. A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Lesnik, P., Haskell, C. A. & Charo, I. F. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J. Clin. Invest. 111, 333–340 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Narahari, A. K. et al. ATP and large signaling metabolites flux through caspase-activated pannexin 1 channels. eLife 10, e64787 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bours, M. J. L., Swennen, E. L. R., Virgilio, F. D., Cronstein, B. N. & Dagnelie, P. C. Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther. 112, 358–404 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Junger, W. G. Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11, 201–212 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Erb, L. & Weisman, G. A. Coupling of P2Y receptors to G proteins and other signaling pathways. Wiley Interdiscip. Rev. Membr. Transp. Signal. 1, 789–803 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kage, F. et al. Lamellipodia-like actin networks in cells lacking WAVE regulatory complex. J. Cell Sci. 135, jcs260364 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kronlage, M. et al. Autocrine purinergic receptor signaling is essential for macrophage chemotaxis. Sci. Signal. 3, ra55 (2010).

    Article  PubMed  Google Scholar 

  84. Hochhauser, E. et al. P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo. Purinergic Signal. 9, 633–642 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen, X. et al. Endothelial cell-specific deletion of P2Y2 receptor promotes plaque stability in atherosclerosis-susceptible ApoE-null mice. Arterioscler. Thromb. Vasc. Biol. 37, 75–83 (2018).

    Article  Google Scholar 

  86. Weiß, E. & Kretschmer, D. Formyl-peptide receptors in infection, inflammation, and cancer. Trends Immunol. 39, 815–829 (2018).

    Article  PubMed  Google Scholar 

  87. McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Yoo, S. K., Starnes, T. W., Deng, Q. & Huttenlocher, A. Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480, 109–112 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nakao, N. et al. Hydrogen peroxide induces the production of tumor necrosis factor-α in RAW 264.7 macrophage cells via activation of p38 and stress-activated protein kinase. Innate Immun. 14, 190–196 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Chekeni, F. B. et al. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467, 863–867 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Elliott, M. R. & Ravichandran, K. S. The dynamics of apoptotic cell clearance. Dev. Cell 38, 147–160 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Virgilio, F. D. Liaisons dangereuses: P2X7 and the inflammasome. Trends Pharmacol. Sci. 28, 465–472 (2007).

    Article  PubMed  Google Scholar 

  93. Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu, M. et al. Simvastatin suppresses vascular inflammation and atherosclerosis in ApoE−/− mice by downregulating the HMGB1-RAGE axis. Acta Pharmacol. Sin. 34, 830–836 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hirata, Y. et al. HMGB1 plays a critical role in vascular inflammation and lesion formation via toll-like receptor 9. Atherosclerosis 231, 227–233 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Wahid, A., Chen, W., Wang, X. & Tang, X. High-mobility group Box 1 serves as an inflammation driver of cardiovascular disease. Biomed. Pharmacother. 139, 111555 (2021).

    Article  CAS  PubMed  Google Scholar 

  97. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Fan, H. et al. Association between plasma growth arrest-specific protein 6 and carotid atherosclerosis in type 2 diabetes mellitus. Nutr. Metab. Cardiovasc. Dis. 32, 1917–1923 (2022).

    Article  CAS  PubMed  Google Scholar 

  99. Ait-Oufella, H. et al. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 1429–1431 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cai, B. et al. MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc. Natl Acad. Sci. USA 113, 6526–6531 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cai, B. et al. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J. Clin. Invest. 127, 564–568 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Tateishi, H. et al. A new inhibitor of ADAM17 composed of a zinc-binding dithiol moiety and a specificity pocket-binding appendage. Chem. Pharm. Bull. 69, 1123–1130 (2021).

    Article  CAS  Google Scholar 

  104. Yancey, P. G. et al. Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler. Thromb. Vasc. Biol. 30, 787–795 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tcheandjieu, C. et al. Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. Nat. Med. 28, 1679–1692 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Canuel, M. et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLoS ONE 8, e64145 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Liu, S. et al. PCSK9 attenuates efferocytosis in endothelial cells and promotes vascular aging. Theranostics 13, 2914–2929 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kojima, Y. et al. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis. J. Clin. Invest. 124, 1083–1097 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Anandan, V. et al. Cyclophilin A impairs efferocytosis and accelerates atherosclerosis by overexpressing CD 47 and down-regulating calreticulin. Cells 10, 3598 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Aragam, K. G. et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat. Genet. 54, 1803–1815 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ait-Oufella, H. et al. Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation 115, 2168–2177 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Jarr, K.-U., Kojima, Y., Weissman, I. L. & Leeper, N. J. 2021 Jeffrey M. Hoeg Award lecture: defining the role of efferocytosis in cardiovascular disease: a focus on the CD47 (cluster of differentiation 47) axis. Arterioscler. Thromb. Vasc. Biol. 42, e145–e154 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl Acad. Sci. USA 109, 6662–6667 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kojima, Y. et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536, 86–90 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kaur, S., Cicalese, K. V., Banerjee, R. & Roberts, D. D. Preclinical and clinical development of therapeutic antibodies targeting functions of CD47 in the tumor microenvironment. Antib. Ther. 3, 179–192 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Pietsch, E. C. et al. Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies. Blood Cancer J. 7, e536 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gilead. Gilead statement on discontinuation of phase 3 ENHANCE-3 study in AML (Gilead, 2024).

  118. Daver, N. G. et al. Tolerability and efficacy of the anticluster of differentiation 47 antibody magrolimab combined with azacitidine in patients with previously untreated AML: phase Ib results. J. Clin. Oncol. 41, 4893–4904 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jarr, K.-U. et al. Effect of CD47 blockade on vascular inflammation. N. Engl. J. Med. 384, 382–383 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Jarr, K.-U. et al. 18F-fluorodeoxyglucose-positron emission tomography imaging detects response to therapeutic intervention and plaque vulnerability in a murine model of advanced atherosclerotic disease – brief report. Arterioscler. Thromb. Vasc. Biol. 40, 2821–2828 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Singla, B. et al. Loss of myeloid cell-specific SIRPα, but not CD47, attenuates inflammation and suppresses atherosclerosis. Cardiovasc. Res. 118, 3097–3111 (2021).

    Article  PubMed Central  Google Scholar 

  122. Tsai, R. K. & Discher, D. E. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J. Cell Biol. 180, 989–1003 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Flores, A. M. et al. Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis. Nat. Nanotechnol. 15, 154–161 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Flores, A. M. et al. Nanoparticle therapy for vascular diseases. Arterioscler. Thromb. Vasc. Biol. 39, 635–646 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wang, X. et al. CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder. Cell Metab. 34, 1088–1103.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Brown, S. et al. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Hsu, Y.-W. et al. Siglec-E retards atherosclerosis by inhibiting CD36-mediated foam cell formation. J. Biomed. Sci. 28, 5 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Barkal, A. A. et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 19, 76–84 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Sinthuwiwat, T. et al. A LILRB1 variant with a decreased ability to phosphorylate SHP-1 leads to autoimmune diseases. Sci. Rep. 12, 15420 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Peng, D. H. et al. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion. Nat. Commun. 11, 4520 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Colin, S., Chinetti‐Gbaguidi, G. & Staels, B. Macrophage phenotypes in atherosclerosis. Immunol. Rev. 262, 153–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Kumar, D., Pandit, R. & Yurdagul, A. Mechanisms of continual efferocytosis by macrophages and its role in mitigating atherosclerosis. Immunometabolism 5, e00017 (2023).

    Article  PubMed  Google Scholar 

  133. Xu, W. et al. IL-10-producing macrophages preferentially clear early apoptotic cells. Blood 107, 4930–4937 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Yurdagul, A. et al. Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury. Cell Metab. 31, 518–533.e10 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cohen, P. L. et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135–140 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lee, Y. et al. Inhibiting Mer receptor tyrosine kinase suppresses STAT1, SOCS1/3, and NF‐κB activation and enhances inflammatory responses in lipopolysaccharide‐induced acute lung injury. J. Leukoc. Biol. 91, 921–932 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Choi, J.-Y. et al. Upregulation of mer receptor tyrosine kinase signaling attenuated lipopolysaccharide-induced lung inflammation. J. Pharmacol. Exp. Ther. 344, 447–458 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Choi, J.-Y. et al. Mer signaling increases the abundance of the transcription factor LXR to promote the resolution of acute sterile inflammation. Sci. Signal. 8, ra21 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Cai, B. et al. MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci. Signal. 11, eaar3721 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Bardin, M. et al. The resolvin D2–GPR18 axis is expressed in human coronary atherosclerosis and transduces atheroprotection in apolipoprotein E deficient mice. Biochem. Pharmacol. 201, 115075 (2022).

    Article  CAS  PubMed  Google Scholar 

  141. Salic, K. et al. Resolvin E1 attenuates atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin. Atherosclerosis 250, 158–165 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Hasturk, H. et al. Resolvin E1 (RvE1) attenuates atherosclerotic plaque formation in diet and inflammation-induced atherogenesis. Arterioscler. Thromb. Vasc. Biol. 35, 1123–1133 (2018).

    Article  Google Scholar 

  143. Polumuri, S., Perkins, D. J. & Vogel, S. N. cAMP levels regulate macrophage alternative activation marker expression. Innate Immun. 27, 133–142 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Shan, K. et al. Resolvin D1 and D2 inhibit tumour growth and inflammation via modulating macrophage polarization. J. Cell. Mol. Med. 24, 8045–8056 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Molaie, M. et al. Imbalanced serum levels of resolvin E1 (RvE1) and leukotriene B4 (LTB4) may contribute to the pathogenesis of atherosclerosis. Prostaglandins Other Lipid Mediat. 169, 106781 (2023).

    Article  CAS  PubMed  Google Scholar 

  146. Zhang, S. et al. Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 29, 443–456.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  147. Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2018).

    Article  PubMed  Google Scholar 

  148. Nissen, S. E. When is a placebo not a placebo. JAMA Cardiol. 7, 1183–1184 (2022).

    Article  PubMed  Google Scholar 

  149. Daida, H. Randomized trial for evaluating secondary prevention efficacy of combination therapy – statin and eicosapentaenoic acid. Circulation 146, e569–e611 (2022).

    Google Scholar 

  150. Lee, Y.-J. et al. STAT6 signaling mediates PPARγ activation and resolution of acute sterile inflammation in mice. Cells 10, 501 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Xian, X. et al. LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis. eLife 6, e29292 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  152. A-Gonzalez, N. et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245–258 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ivanov, S. et al. Lysosomal cholesterol hydrolysis couples efferocytosis to anti-inflammatory oxysterol production. Atherosclerosis 287, e77 (2019).

    Article  Google Scholar 

  154. Endo-Umeda, K. et al. Myeloid LXR (liver X receptor) deficiency induces inflammatory gene expression in foamy macrophages and accelerates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 42, 719–731 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Yurdagul, A. Jr et al. ODC (ornithine decarboxylase)-dependent putrescine synthesis maintains MerTK (MER yrosine-protein kinase) expression to drive resolution. Arterioscler. Thromb. Vasc. Biol. 41, e144–e159 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Cai, W. et al. STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice. JCI Insight 4, e131355 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Morioka, S. et al. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563, 714–718 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Wang, Y.-T. et al. Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments. Cell Metab. 35, 316–331.e6 (2023).

    Article  PubMed  Google Scholar 

  159. Schrijvers, D. M., Meyer, G. R. Y.De, Kockx, M. M., Herman, A. G. & Martinet, W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 25, 1256–1261 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Yurdagul, A., Doran, A. C., Cai, B., Fredman, G. & Tabas, I. A. Mechanisms and consequences of defective efferocytosis in atherosclerosis. Front. Cardiovasc. Med. 4, 86 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Silvestre-Roig, C. et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature 569, 236–240 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Kockx, M. M. et al. Apoptosis and related proteins in different stages of human atherosclerotic plaques. Circulation 97, 2307–2315 (1998).

    Article  CAS  PubMed  Google Scholar 

  163. Yvan-Charvet, L. et al. ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis. Circ. Res. 106, 1861–1869 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kannan, K. & Jain, S. K. Oxidative stress and apoptosis. Pathophysiology 7, 153–163 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Sachet, M., Liang, Y. Y. & Oehler, R. The immune response to secondary necrotic cells. Apoptosis 22, 1189–1204 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wright, M. B. et al. Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease. Nat. Commun. 12, 4662 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hoeffner, N., Paul, A. & Goo, Y.-H. Drug screen identifies verteporfin as a regulator of lipid metabolism in macrophage foam cells. Sci. Rep. 13, 19588 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Tabas, I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 25, 2255–2264 (2005).

    Article  CAS  PubMed  Google Scholar 

  169. Sambrano, G. R., Parthasarathy, S. & Steinberg, D. Recognition of oxidatively damaged erythrocytes by a macrophage receptor with specificity for oxidized low density lipoprotein. Proc. Natl Acad. Sci. USA 91, 3265–3269 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sambrano, G. R. & Steinberg, D. Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine. Proc. Natl Acad. Sci. USA 92, 1396–1400 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Miller, Y. I. et al. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J. Biol. Chem. 278, 1561–1568 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Wu, R. & Lefvert, A. K. Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL. Clin. Exp. Immunol. 102, 174–180 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Chang, M.-K. et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc. Natl Acad. Sci. USA 96, 6353–6358 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Fraser, D. A. & Tenner, A. J. Innate immune proteins C1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages. J. Immunol. 185, 3932–3939 (2010).

    Article  CAS  PubMed  Google Scholar 

  175. Duus, K. et al. Direct interaction between CD91 and C1q. FEBS J. 277, 3526–3537 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Pulanco, M. C. et al. Complement protein C1q enhances macrophage foam cell survival and efferocytosis. J. Immunol. 198, 472–480 (2017).

    Article  CAS  PubMed  Google Scholar 

  177. Kojima, Y. et al. Proefferocytic therapy promotes transforming growth factor-β signaling and prevents aneurysm formation. Circulation 137, 750–753 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Betancur, P. A. et al. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Nat. Commun. 8, 14802 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Zhang, X. et al. Blocking CD47 efficiently potentiated therapeutic effects of anti-angiogenic therapy in non-small cell lung cancer. J. Immunother. Cancer 7, 346 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Bruunsgaard, H., Skinhøj, P., Pedersen, A. N., Schroll, M. & Pedersen, B. K. Ageing, tumour necrosis factor‐alpha (TNF‐α) and atherosclerosis. Clin. Exp. Immunol. 121, 255–260 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Kohno, K. et al. Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells. J. Inflamm. 18, 2 (2021).

    Article  CAS  Google Scholar 

  182. Paul, B. et al. A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma. Futur. Oncol. 19, 7–17 (2023).

    Article  CAS  Google Scholar 

  183. Sallman, D. A. et al. Magrolimab in combination with azacitidine in patients with higher-risk myelodysplastic syndromes: final results of a phase Ib study. J. Clin. Oncol. 41, 2815–2826 (2023).

    Article  CAS  PubMed  Google Scholar 

  184. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04827576 (2024).

  185. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02216409 (2019).

  186. Wong, D. et al. FHL5 controls vascular disease-associated gene programs in smooth muscle cells. Circ. Res. 132, 1144–1161 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Mosquera, J. V. et al. Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis. Cell Rep. 42, 113380 (2023).

    Article  CAS  PubMed  Google Scholar 

  188. Pan, H. et al. Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human. Circulation 142, 2060–2075 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Luo, L., Fu, C., Bell, C. F., Wang, Y. & Leeper, N. J. Role of vascular smooth muscle cell clonality in atherosclerosis. Front. Cardiovasc. Med. 10, 1273596 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Sihombing, M. A. E. M. et al. Unexpected role of nonimmune cells: amateur phagocytes. DNA Cell Biol. 40, 157–171 (2021).

    Article  CAS  PubMed  Google Scholar 

  191. Kirsch, T. et al. Engulfment of apoptotic cells by microvascular endothelial cells induces proinflammatory responses. Blood 109, 2854–2862 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Shankman, L. S. et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat. Med. 21, 628–637 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Wernig, G. et al. Unifying mechanism for different fibrotic diseases. Proc. Natl Acad. Sci. USA 114, 4757–4762 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Hear. J. 38, 187–197 (2017).

    CAS  Google Scholar 

  196. Peet, C., Ivetic, A., Bromage, D. I. & Shah, A. M. Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc. Res. 116, 1101–1112 (2020).

    Article  CAS  PubMed  Google Scholar 

  197. Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 29–39 (2019).

    Article  CAS  PubMed  Google Scholar 

  198. Vagnozzi, R. J. et al. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature 577, 405–409 (2020).

    Article  CAS  PubMed  Google Scholar 

  199. Roma-Lavisse, C. et al. M1 and M2 macrophage proteolytic and angiogenic profile analysis in atherosclerotic patients reveals a distinctive profile in type 2 diabetes. Diabetes Vasc. Dis. Res. 12, 279–289 (2015).

    Article  CAS  Google Scholar 

  200. DeBerge, M. et al. MerTK cleavage on resident cardiac macrophages compromises repair after myocardial ischemia reperfusion injury. Circ. Res. 121, 930–940 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Deng, K.-Q. et al. Restoration of circulating MFGE8 (milk fat globule-EGF factor 8) attenuates cardiac hypertrophy through inhibition of Akt pathway. Hypertension 70, 770–779 (2018).

    Article  Google Scholar 

  202. Zhang, S. et al. Acute CD47 blockade during ischemic myocardial reperfusion enhances phagocytosis-associated cardiac repair. JACC Basic. Transl. Sci. 2, 386–397 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Mahmoudi, A. et al. Effect of diabetes on efferocytosis process. Mol. Biol. Rep. 49, 10849–10863 (2022).

    Article  CAS  PubMed  Google Scholar 

  204. Maschalidi, S. et al. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes. Nature 606, 776–784 (2022).

    Article  CAS  PubMed  Google Scholar 

  205. Harris, M. I. Hypercholesterolemia in diabetes and glucose intolerance in the U.S. population. Diabetes Care 14, 366–374 (1991).

    Article  CAS  PubMed  Google Scholar 

  206. Hu, X. et al. The role of remnant cholesterol beyond low-density lipoprotein cholesterol in diabetes mellitus. Cardiovasc. Diabetol. 21, 117 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Hirano, T. Pathophysiology of diabetic dyslipidemia. J. Atheroscler. Thromb. 25, RV17023 (2018).

    Article  Google Scholar 

  208. Okdahl, T. et al. Low-grade inflammation in type 2 diabetes: a cross-sectional study from a Danish diabetes outpatient clinic. BMJ Open. 12, e062188 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Fiorentino, T., Prioletta, A., Zuo, P. & Folli, F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr. Pharm. Des. 19, 5695–5703 (2013).

    Article  CAS  PubMed  Google Scholar 

  210. Tseng, H. H. L., Vong, C. T., Kwan, Y. W., Lee, S. M.-Y. & Hoi, M. P. M. TRPM2 regulates TXNIP-mediated NLRP3 inflammasome activation via interaction with p47 phox under high glucose in human monocytic cells. Sci. Rep. 6, 35016 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Ye, J. et al. Diabetes mellitus promotes the development of atherosclerosis: the role of NLRP3. Front. Immunol. 13, 900254 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Crasto, W., Patel, V., Davies, M. J. & Khunti, K. Prevention of microvascular complications of diabetes. Endocrinol. Metab. Clin. North. Am. 50, 431–455 (2021).

    Article  PubMed  Google Scholar 

  213. Salman, H., Bergman, M., Djaldetti, M. & Bessler, H. Hydrophobic but not hydrophilic statins enhance phagocytosis and decrease apoptosis of human peripheral blood cells in vitro. Biomed. Pharmacother. 62, 41–45 (2008).

    Article  CAS  PubMed  Google Scholar 

  214. Morimoto, K. et al. Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J. Immunol. 176, 7657–7665 (2006).

    Article  CAS  PubMed  Google Scholar 

  215. Sahai, E. & Marshall, C. J. RHO-GTPases and cancer. Nat. Rev. Cancer 2, 133–142 (2002).

    Article  PubMed  Google Scholar 

  216. Tajbakhsh, A. et al. Statin-regulated phagocytosis and efferocytosis in physiological and pathological conditions. Pharmacol. Ther. 238, 108282 (2022).

    Article  CAS  PubMed  Google Scholar 

  217. Jarr, K.-U. et al. The pleiotropic benefits of statins include the ability to reduce CD47 and amplify the effect of pro-efferocytic therapies in atherosclerosis. Nat. Cardiovasc. Res. 1, 253–262 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Cannon, C. P. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 1495–1504 (2004); correction 354, 778 (2006).

    Article  Google Scholar 

  219. Chan, A. W. et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation 105, 691–696 (2002).

    Article  CAS  PubMed  Google Scholar 

  220. Ray, K. K. & Cannon, C. P. Time to benefit: an emerging concept for assessing the efficacy of statin therapy in cardiovascular disease. Crit. Pathw. Cardiol. 4, 43–45 (2005).

    Article  PubMed  Google Scholar 

  221. McInnes, G., Yee, S. W., Pershad, Y. & Altman, R. B. Genomewide association studies in pharmacogenomics. Clin. Pharmacol. Ther. 110, 637–648 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Motsinger-Reif, A. A. et al. Genome-wide association studies in pharmacogenomics. Pharmacogenet. Genom. 23, 383–394 (2013).

    Article  CAS  Google Scholar 

  223. Nanda, V. et al. CDKN2B regulates TGFβ signaling and smooth muscle cell investment of hypoxic neovessels. Circ. Res. 118, 230–240 (2016).

    Article  CAS  PubMed  Google Scholar 

  224. Kasikara, C. et al. Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. J. Clin. Invest. 131, e145275 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Alsheikh, A. J. et al. The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases. BMC Med. Genom. 15, 74 (2022).

    Article  Google Scholar 

  226. Feehley, T., O’Donnell, C. W., Mendlein, J., Karande, M. & McCauley, T. Drugging the epigenome in the age of precision medicine. Clin. Epigenetics 15, 6 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Cappelluti, M. A. et al. Durable and efficient gene silencing in vivo by hit-and-run epigenome editing. Nature 627, 416–423 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Klann, T. S. et al. CRISPR–Cas9 epigenome editing enables high-throughput screening for functional regulatory elements in the human genome. Nat. Biotechnol. 35, 561–568 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Wennogle, L. P. et al. Comparison of recombinant cyclooxygenase‐2 to native isoforms: aspirin labeling of the active site. FEBS Lett. 371, 315–320 (1995).

    Article  CAS  PubMed  Google Scholar 

  230. Yoo, S. G. K. et al. Aspirin for secondary prevention of cardiovascular disease in 51 low-, middle-, and high-income countries. JAMA 330, 715–724 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Minikel, E. V. et al. Evaluating drug targets through human loss-of-function genetic variation. Nature 581, 459–464 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Morioka, S. et al. Chimeric efferocytic receptors improve apoptotic cell clearance and alleviate inflammation. Cell 185, 4887–4903.e17 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Lafont, A. Basic aspects of plaque vulnerability. Heart 89, 1262 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  234. McDermott, D. H. et al. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J. Clin. Invest. 111, 1241–1250 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Friggeri, A. et al. HMGB1 inhibits macrophage activity in efferocytosis through binding to the αvβ3-integrin. Am. J. Physiol. Cell Physiol. 299, C1267–C1276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Chen, W. et al. The ABCA1-efferocytosis axis: a new strategy to protect against atherosclerosis. Clin. Chim. Acta 518, 1–8 (2021).

    Article  CAS  PubMed  Google Scholar 

  237. Rong, J. et al. Lysophasphatidylcholine stimulates monocyte chemoattractant protein-1 gene expression in rat aortic smooth muscle cells. Asterioscler. Thromb. Vasc. Biol. 22, 1617–1623 (2008).

    Article  Google Scholar 

  238. Gude, D. R. et al. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine‐1‐phosphate as a “come‐and‐get‐me” signal. FASEB J. 22, 2629–2638 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Galvani, S. et al. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci. Signal. 8, ra79 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Bhatia, V. K. et al. Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am. J. Pathol. 170, 416–426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Kourtzelis, I. et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat. Immunol. 20, 40–49 (2019).

    Article  CAS  PubMed  Google Scholar 

  242. Kakino, A., Fujita, Y., Nakano, A., Horiuchi, S. & Sawamura, T. Developmental endothelial locus-1 (Del-1) inhibits oxidized low-density lipoprotein activity by direct binding, and its overexpression attenuates atherogenesis in mice. Circ. J. 80, 2541–2549 (2016).

    Article  CAS  PubMed  Google Scholar 

  243. van der Meer, J. H., van der Poll, T. & van ‘t Veer, C. TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis. Blood 123, 2460–2469 (2014).

    Article  PubMed  Google Scholar 

  244. Lutgens, E. et al. Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis. J. Pathol. 216, 55–63 (2008).

    Article  CAS  PubMed  Google Scholar 

  245. Robins, R. S. et al. Vascular Gas6 contributes to thrombogenesis and promotes tissue factor up-regulation after vessel injury in mice. Blood 121, 692–699 (2013).

    Article  CAS  PubMed  Google Scholar 

  246. Tang, Y. et al. Mertk deficiency affects macrophage directional migration via disruption of cytoskeletal organization. PLoS ONE 10, e0117787 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Park, D., Hochreiter-Hufford, A. & Ravichandran, K. S. The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Curr. Biol. 19, 346–351 (2009).

    Article  PubMed  Google Scholar 

  248. Moon, B. et al. Mertk interacts with Tim-4 to enhance Tim-4-mediated efferocytosis. Cells 9, 1625 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Foks, A. C. et al. Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor–deficient mice. Arterioscler. Thromb. Vasc. Biol. 36, 456–465 (2018).

    Article  Google Scholar 

  250. Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007).

    Article  CAS  PubMed  Google Scholar 

  251. Fond, A. M., Lee, C. S., Schulman, I. G., Kiss, R. S. & Ravichandran, K. S. Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1. J. Clin. Invest. 125, 2748–2758 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  252. Park, S.-Y. et al. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 15, 192–201 (2008).

    Article  CAS  PubMed  Google Scholar 

  253. Kayashima, Y. et al. Reduction of stabilin-2 contributes to a protection against atherosclerosis. Front. Cardiovasc. Med. 9, 818662 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Jenkins, W. S. et al. In vivo alpha-V beta-3 integrin expression in human aortic atherosclerosis. Heart 105, 1868–1875 (2019).

    Article  CAS  PubMed  Google Scholar 

  255. Tao, H. et al. Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J. Lipid Res. 56, 1449–1460 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Falasca, L. et al. Transglutaminase type II is a key element in the regulation of the anti-inflammatory response elicited by apoptotic cell engulfment. J. Immunol. 174, 7330–7340 (2005).

    Article  CAS  PubMed  Google Scholar 

  257. Thorp, E., Subramanian, M. & Tabas, I. The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis. Eur. J. Immunol. 41, 2515–2518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Boisvert, W. A. et al. Leukocyte transglutaminase 2 expression limits atherosclerotic lesion size. Arterioscler. Thromb. Vasc. Biol. 26, 563–569 (2006).

    Article  CAS  PubMed  Google Scholar 

  259. Isner, J. M., Kearney, M., Bortman, S. & Passeri, J. Apoptosis in human atherosclerosis and restenosis. Circulation 91, 2703–2711 (1995).

    Article  CAS  PubMed  Google Scholar 

  260. Henderson, N. C., Rieder, F. & Wynn, T. A. Fibrosis: from mechanisms to medicines. Nature 587, 555–566 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Morimoto, K., Janssen, W. J. & Terada, M. Defective efferocytosis by alveolar macrophages in IPF patients. Respir. Med. 106, 1800–1803 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  262. Shi, H. et al. CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis. Sci. Transl. Med. 14, eabp8309 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Li, Y. et al. CD47 antibody suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy. Am. J. Transl. Res. 12, 5908–5923 (2019).

    Google Scholar 

Download references

Acknowledgements

N.J.L. is supported by the grants NIH R35HL 144475 and AHA EIA34770065, the Leducq Foundation, the Falk Foundation, and the Greathouse Family Foundation. S.S.A. is supported by the grant NIH T32HL 98049-13.

Author information

Authors and Affiliations

  1. Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA

    Shaunak S. Adkar & Nicholas J. Leeper

  2. Stanford Cardiovascular Institute, Stanford, CA, USA

    Shaunak S. Adkar & Nicholas J. Leeper

Authors
  1. Shaunak S. Adkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas J. Leeper
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed substantially to all aspects of the article.

Corresponding author

Correspondence to Nicholas J. Leeper.

Ethics declarations

Competing interests

N.J.L. is co-founder and director of Bitterroot Bio, a biotechnology company focused on immunomodulatory therapies for cardiovascular disease. S.S.A. declares no competing interests.

Peer review

Peer review information

Nature Reviews Cardiology thanks Amanda C. Doran, MacRae F. Linton, and Manikandan Subramanian for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adkar, S.S., Leeper, N.J. Efferocytosis in atherosclerosis. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-01037-7

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41569-024-01037-7

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing