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  • Review Article
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Targeting immune cell recruitment in atherosclerosis

Nature Reviews Cardiology (2024)Cite this article

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Abstract

Atherosclerosis is the primary underlying cause of myocardial infarction and stroke. Atherosclerotic cardiovascular disease is characterized by a chronic inflammatory reaction in medium-to-large-sized arteries, with its onset and perpetuation driven by leukocytes infiltrating the subendothelial space. Activation of endothelial cells triggered by hyperlipidaemia and lipoprotein retention in the arterial intima initiates the accumulation of pro-inflammatory leukocytes in the arterial wall, fostering the progression of atherosclerosis. This inflammatory response is coordinated by an array of soluble mediators, namely cytokines and chemokines, that amplify inflammation both locally and systemically and are complemented by tissue-specific molecules that regulate the homing, adhesion and transmigration of leukocytes. Despite abundant evidence from mouse models, only a few therapies targeting leukocytes in atherosclerosis have been assessed in humans. The major challenges for the clinical translation of these therapies include the lack of tissue specificity and insufficient selectivity of inhibition strategies. In this Review, we discuss the latest research on receptor–ligand pairs and interactors that regulate leukocyte influx into the inflamed artery wall, primarily focusing on studies that used pharmacological interventions. We also discuss mechanisms that promote the resolution of inflammation and highlight how major findings from these research areas hold promise as potential therapeutic strategies for atherosclerotic cardiovascular disease.

Key points

  • Preclinical studies have demonstrated that targeting of chemokine–chemokine receptor pathways is a promising therapeutic approach, although additional clinical studies are required to validate the potential of these approaches.

  • Formation of heterodimers of chemokines and chemokine receptors provides an additional layer of complexity in the chemokine–receptor network, which has so far been underestimated and might offer refined therapeutic potential in the future.

  • Circadian rhythmicity of leukocyte migration patterns is an important mechanism that remains undervalued and should be considered when devising clinical interventions to target leukocyte recruitment.

  • Fostering the resolution of inflammation by supplementation with polyunsaturated fatty acids has shown benefits in preclinical and clinical studies, although targeted delivery approaches should be developed to improve efficacy.

  • Despite promising findings from preclinical studies, IL-10 supplementation and transfer of regulatory T cells have not yet been assessed in the clinical setting and thus warrant future study.

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Fig. 1: Therapeutic approaches targeting chemokines and chemokine receptors in atherosclerotic cardiovascular disease.
Fig. 2: SPMs and resolution of inflammation.
Fig. 3: SPMs as a therapeutic approach to modulate leukocyte recruitment to atherosclerotic plaques.

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References

  1. Bjorkegren, J. L. M. & Lusis, A. J. Atherosclerosis: recent developments. Cell 185, 1630–1645 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. van der Vorst, E. P. C. et al. G-protein coupled receptor targeting on myeloid cells in atherosclerosis. Front. Pharmacol. 10, 531 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Yan, Y., Thakur, M., van der Vorst, E. P. C., Weber, C. & Doring, Y. Targeting the chemokine network in atherosclerosis. Atherosclerosis 330, 95–106 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Soehnlein, O. & Libby, P. Targeting inflammation in atherosclerosis — from experimental insights to the clinic. Nat. Rev. Drug Discov. 20, 589–610 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gencer, S., Evans, B. R., van der Vorst, E. P. C., Doring, Y. & Weber, C. Inflammatory chemokines in atherosclerosis. Cells 10, 226 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lutgens, E. et al. Immunotherapy for cardiovascular disease. Eur. Heart J. 40, 3937–3946 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Noels, H., Weber, C. & Koenen, R. R. Chemokines as therapeutic targets in cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 39, 583–592 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Blanchet, X., Weber, C. & von Hundelshausen, P. Chemokine heteromers and their impact on cellular function-a conceptual framework. Int. J. Mol. Sci. 24, 10925 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gencer, S. et al. Atypical chemokine receptors in cardiovascular disease. Thromb. Haemost. 119, 534–541 (2019).

    Article  PubMed  Google Scholar 

  12. Doran, A. C. Inflammation resolution: implications for atherosclerosis. Circ. Res. 130, 130–148 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Back, M., Yurdagul, A. Jr., Tabas, I., Oorni, K. & Kovanen, P. T. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat. Rev. Cardiol. 16, 389–406 (2019).

    PubMed  PubMed Central  Google Scholar 

  14. Basil, M. C. & Levy, B. D. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat. Rev. Immunol. 16, 51–67 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Serhan, C. N. & Levy, B. D. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J. Clin. Invest. 128, 2657–2669 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Norling, L. V., Dalli, J., Flower, R. J., Serhan, C. N. & Perretti, M. Resolvin D1 limits polymorphonuclear leukocyte recruitment to inflammatory loci: receptor-dependent actions. Arterioscler. Thromb. Vasc. Biol. 32, 1970–1978 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sansbury, B. E. & Spite, M. Resolution of acute inflammation and the role of resolvins in immunity, thrombosis, and vascular biology. Circ. Res. 119, 113–130 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Maganto-Garcia, E. et al. Foxp3+-inducible regulatory T cells suppress endothelial activation and leukocyte recruitment. J. Immunol. 187, 3521–3529 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Akkaya, B. et al. Regulatory T cells mediate specific suppression by depleting peptide-MHC class II from dendritic cells. Nat. Immunol. 20, 218–231 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Subramanian, M., Thorp, E., Hansson, G. K. & Tabas, I. Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J. Clin. Invest. 123, 179–188 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Ring, S., Schafer, S. C., Mahnke, K., Lehr, H. A. & Enk, A. H. CD4+ CD25+ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue. Eur. J. Immunol. 36, 2981–2992 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Pinderski Oslund, L. J. et al. Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol. 19, 2847–2853 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Raffin, C., Vo, L. T. & Bluestone, J. A. Treg cell-based therapies: challenges and perspectives. Nat. Rev. Immunol. 20, 158–172 (2020).

    Article  CAS  PubMed  Google Scholar 

  24. Saraiva, M., Vieira, P. & O’Garra, A. Biology and therapeutic potential of interleukin-10. J. Exp. Med. 217, e20190418 (2020).

    Article  PubMed  Google Scholar 

  25. Zhang, H. et al. Role of the CCL2-CCR2 axis in cardiovascular disease: pathogenesis and clinical implications. Front. Immunol. 13, 975367 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bot, I. et al. A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy. Sci. Rep. 7, 52 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zivkovic, L., Asare, Y., Bernhagen, J., Dichgans, M. & Georgakis, M. K. Pharmacological targeting of the CCL2/CCR2 axis for atheroprotection: a meta-analysis of preclinical studies. Arterioscler. Thromb. Vasc. Biol. 42, e131–e144 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Georgakis, M. K. et al. Carriers of rare damaging CCR2 genetic variants are at lower risk of atherosclerotic disease. Preprint at medRxiv https://doi.org/10.1101/2023.08.14.23294063 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gilbert, J. et al. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am. J. Cardiol. 107, 906–911 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Lim, S. Y., Yuzhalin, A. E., Gordon-Weeks, A. N. & Muschel, R. J. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget 7, 28697–28710 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Obmolova, G. et al. Structural basis for high selectivity of anti-CCL2 neutralizing antibody CNTO 888. Mol. Immunol. 51, 227–233 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Kirk, P. S. et al. Inhibition of CCL2 signaling in combination with docetaxel treatment has profound inhibitory effects on prostate cancer growth in bone. Int. J. Mol. Sci. 14, 10483–10496 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Loberg, R. D. et al. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res. 67, 9417–9424 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Pienta, K. J. et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest. New Drugs 31, 760–768 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Pekayvaz, K. et al. Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation. Immunity 56, 2325–2341.e15 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cipriani, S. et al. Efficacy of the CCR5 antagonist maraviroc in reducing early, ritonavir-induced atherogenesis and advanced plaque progression in mice. Circulation 127, 2114–2124 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Francisci, D. et al. Maraviroc intensification modulates atherosclerotic progression in HIV-suppressed patients at high cardiovascular risk. a randomized, crossover pilot study. Open Forum Infect. Dis. 6, ofz112 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Maggi, P. et al. Effects of therapy with maraviroc on the carotid intima media thickness in HIV-1/HCV co-infected patients. In Vivo 31, 125–131 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Galkina, E. et al. CXCR6 promotes atherosclerosis by supporting T-cell homing, interferon-γ production, and macrophage accumulation in the aortic wall. Circulation 116, 1801–1811 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Butcher, M. J., Wu, C. I., Waseem, T. & Galkina, E. V. CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas. Int. Immunol. 28, 255–261 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Nordlohne, J. & von Vietinghoff, S. Interleukin 17A in atherosclerosis — regulation and pathophysiologic effector function. Cytokine 122, 154089 (2019).

    Article  PubMed  Google Scholar 

  42. Butcher, M. J., Waseem, T. C. & Galkina, E. V. Smooth muscle cell-derived interleukin-17C plays an atherogenic role via the recruitment of proinflammatory interleukin-17A+ T cells to the aorta. Arterioscler. Thromb. Vasc. Biol. 36, 1496–1506 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hou, L. et al. SerpinB1 controls encephalitogenic T helper cells in neuroinflammation. Proc. Natl Acad. Sci. USA 116, 20635–20643 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Szentes, V., Gazdag, M., Szokodi, I. & Dezsi, C. A. The role of CXCR3 and associated chemokines in the development of atherosclerosis and during myocardial infarction. Front. Immunol. 9, 1932 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  45. van Wanrooij, E. J. et al. CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 28, 251–257 (2008).

    Article  PubMed  Google Scholar 

  46. Heller, E. A. et al. Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells. Circulation 113, 2301–2312 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Prapiadou, S. et al. Proteogenomic data integration reveals CXCL10 as a potentially downstream causal mediator for IL-6 signaling on atherosclerosis. Circulation https://doi.org/10.1161/CIRCULATIONAHA.123.064974 (2023).

    Article  PubMed  Google Scholar 

  48. Nitz, K. et al. The amino acid homoarginine inhibits atherogenesis by modulating T-cell function. Circ. Res. 131, 701–712 (2022).

    Article  CAS  PubMed  Google Scholar 

  49. Koch, V. et al. Homoarginine in the cardiovascular system: pathophysiology and recent developments. Fundam. Clin. Pharmacol. 37, 519–529 (2023).

    Article  CAS  PubMed  Google Scholar 

  50. Atzler, D. et al. Oral supplementation with L-homoarginine in young volunteers. Br. J. Clin. Pharmacol. 82, 1477–1485 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wu, J. et al. Two polymorphisms in the Fractalkine receptor CX3CR1 gene influence the development of atherosclerosis: a meta-analysis. Dis. Markers 2014, 913678 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Moatti, D. et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood 97, 1925–1928 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. McDermott, D. H. et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ. Res. 89, 401–407 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Poupel, L. et al. Pharmacological inhibition of the chemokine receptor, CX3CR1, reduces atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 33, 2297–2305 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Low, S. et al. VHH antibody targeting the chemokine receptor CX3CR1 inhibits progression of atherosclerosis. mAbs 12, 1709322 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ali, M. T. et al. A novel CX3CR1 antagonist eluting stent reduces stenosis by targeting inflammation. Biomaterials 69, 22–29 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Pyo, R. et al. Inhibition of intimal hyperplasia in transgenic mice conditionally expressing the chemokine-binding protein M3. Am. J. Pathol. 164, 2289–2297 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ravindran, D. et al. Chemokine binding protein ‘M3’ limits atherosclerosis in apolipoprotein E-/- mice. PLoS One 12, e0173224 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ma, S. et al. E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis. Sci. Rep. 6, 22910 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cimen, I. et al. Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice. Sci. Transl. Med. 15, eadf3357 (2023).

    Article  CAS  PubMed  Google Scholar 

  61. Doring, Y. et al. Vascular CXCR4 limits atherosclerosis by maintaining arterial integrity: evidence from mouse and human studies. Circulation 136, 388–403 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Schols, D. et al. Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J. Exp. Med. 186, 1383–1388 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liles, W. C. et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 102, 2728–2730 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Lack, N. A. et al. A pharmacokinetic-pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100. Clin. Pharmacol. Ther. 77, 427–436 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Caspar, B. et al. CXCR4 as a novel target in immunology: moving away from typical antagonists. Future Drug Discov. 4, FDD77 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bot, I. et al. CXCR4 blockade induces atherosclerosis by affecting neutrophil function. J. Mol. Cell Cardiol. 74, 44–52 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Doring, Y. et al. B-cell-specific CXCR4 protects against atherosclerosis development and increases plasma IgM levels. Circ. Res. 126, 787–788 (2020).

    Article  PubMed  Google Scholar 

  68. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT01905475 (2016).

  69. Rajasekaran, D. et al. Macrophage migration inhibitory factor-CXCR4 receptor interactions: evidence for partial allosteric agonism in comparison with CXCL12 chemokine. J. Biol. Chem. 291, 15881–15895 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lacy, M. et al. Identification of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the cytokine MIF and the chemokine receptor CXCR4. Sci. Rep. 8, 5171 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kontos, C. et al. Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting. Nat. Commun. 11, 5981 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mehta, N. N. et al. The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels. Eur. Heart J. 32, 963–971 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Doring, Y. et al. CXCL12 derived from endothelial cells promotes atherosclerosis to drive coronary artery disease. Circulation 139, 1338–1340 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Chung, E. S. et al. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized phase II trial. Eur. Heart J. 36, 2228–2238 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Li, X. et al. Activation of CXCR7 limits atherosclerosis and improves hyperlipidemia by increasing cholesterol uptake in adipose tissue. Circulation 129, 1244–1253 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Cebo, M. et al. Platelet ACKR3/CXCR7 favors antiplatelet lipids over an atherothrombotic lipidome and regulates thromboinflammation. Blood 139, 1722–1742 (2022).

    Article  CAS  PubMed  Google Scholar 

  77. Zhang, S. et al. Activation of CXCR7 alleviates cardiac insufficiency after myocardial infarction by promoting angiogenesis and reducing apoptosis. Biomed. Pharmacother. 127, 110168 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Jurcevic, S. et al. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions. Br. J. Clin. Pharmacol. 80, 1324–1336 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Joseph, J. P. et al. CXCR2 inhibition — a novel approach to treating coronary heart disease (CICADA): study protocol for a randomised controlled trial. Trials 18, 473 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  80. van der Vorst, E. P. C. et al. Interruption of the CXCL13/CXCR5 chemokine axis enhances plasma IgM levels and attenuates atherosclerosis development. Thromb. Haemost. 120, 344–347 (2020).

    Article  PubMed  Google Scholar 

  81. Vanderleyden, I. et al. Follicular regulatory T cells can access the germinal center independently of CXCR5. Cell Rep. 30, 611–619.e4 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Heinrichs, M. et al. The healing myocardium mobilizes a distinct B-cell subset through a CXCL13-CXCR5-dependent mechanism. Cardiovasc. Res. 117, 2664–2676 (2021).

    CAS  PubMed  Google Scholar 

  84. Manthey, H. D. et al. CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice. Thromb. Haemost. 110, 1267–1277 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Doran, A. C. et al. B-cell aortic homing and atheroprotection depend on Id3. Circ. Res. 110, e1–e12 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Singh, A. et al. CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization. Front. Immunol. https://doi.org/10.3389/fimmu.2024.1327051 (2024).

  87. Lorchner, H. et al. Neutrophils for revascularization require activation of CCR6 and CCL20 by TNFα. Circ. Res. 133, 592–610 (2023).

    Article  PubMed  Google Scholar 

  88. Schumacher, D. et al. CCR6 deficiency increases infarct size after murine acute myocardial infarction. Biomedicines 9, 1532 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gomez-Melero, S. & Caballero-Villarraso, J. CCR6 as a potential target for therapeutic antibodies for the treatment of inflammatory diseases. Antibodies 12, 30 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Koenen, R. R. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat. Med. 15, 97–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Fan, Y. et al. MKEY, a peptide inhibitor of CXCL4-CCL5 heterodimer formation, protects against stroke in mice. J. Am. Heart Assoc. 5, e003615 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. von Hundelshausen, P. et al. Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation. Sci. Transl. Med. 9, eaah6650 (2017).

    Article  Google Scholar 

  93. Alard, J. E. et al. Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5. Sci. Transl. Med. 7, 317ra196 (2015).

    Article  PubMed  Google Scholar 

  94. Brandhofer, M. et al. Heterocomplexes between the atypical chemokine MIF and the CXC-motif chemokine CXCL4L1 regulate inflammation and thrombus formation. Cell Mol. Life Sci. 79, 512 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Walsh, T. G., Harper, M. T. & Poole, A. W. SDF-1α is a novel autocrine activator of platelets operating through its receptor CXCR4. Cell Signal. 27, 37–46 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shenkman, B. et al. Differential response of platelets to chemokines: RANTES non-competitively inhibits stimulatory effect of SDF-1α. J. Thromb. Haemost. 2, 154–160 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Leberzammer, J. et al. Targeting platelet-derived CXCL12 impedes arterial thrombosis. Blood 139, 2691–2705 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Eckardt, V. et al. Chemokines and galectins form heterodimers to modulate inflammation. EMBO Rep. 21, e47852 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Buurma, M., van Diemen, J. J. K., Thijs, A., Numans, M. E. & Bonten, T. N. Circadian rhythm of cardiovascular disease: the potential of chronotherapy with aspirin. Front. Cardiovasc. Med. 6, 84 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Thosar, S. S., Butler, M. P. & Shea, S. A. Role of the circadian system in cardiovascular disease. J. Clin. Invest. 128, 2157–2167 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Takeda, N. & Maemura, K. The role of clock genes and circadian rhythm in the development of cardiovascular diseases. Cell Mol. Life Sci. 72, 3225–3234 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yang, G. et al. Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival. Sci. Transl. Med. 8, 324ra316 (2016).

    Article  Google Scholar 

  104. Pan, X., Jiang, X. C. & Hussain, M. M. Impaired cholesterol metabolism and enhanced atherosclerosis in clock mutant mice. Circulation 128, 1758–1769 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shimba, S. et al. Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One 6, e25231 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Winter, C. & Soehnlein, O. The potential of chronopharmacology for treatment of atherosclerosis. Curr. Opin. Lipidol. 29, 368–374 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Nguyen, K. D. et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6Chi inflammatory monocytes. Science 341, 1483–1488 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Curtis, A. M., Bellet, M. M., Sassone-Corsi, P. & O’Neill, L. A. Circadian clock proteins and immunity. Immunity 40, 178–186 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Hergenhan, S., Holtkamp, S. & Scheiermann, C. Molecular interactions between components of the circadian clock and the immune system. J. Mol. Biol. 432, 3700–3713 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Winter, C. et al. Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell Metab. 28, 175–182.e5 (2018).

    Article  CAS  PubMed  Google Scholar 

  111. Pan, C. et al. Time-restricted feeding enhances early atherosclerosis in hypercholesterolemic mice. Circulation 147, 774–777 (2023).

    Article  PubMed  Google Scholar 

  112. In Het Panhuis, W. et al. Time-restricted feeding attenuates hypercholesterolaemia and atherosclerosis development during circadian disturbance in APOE *3-Leiden.CETP mice. EBioMedicine 93, 104680 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Panigrahy, D., Gilligan, M. M., Serhan, C. N. & Kashfi, K. Resolution of inflammation: an organizing principle in biology and medicine. Pharmacol. Ther. 227, 107879 (2021).

    Article  CAS  PubMed  Google Scholar 

  114. Lubrano, V., Ndreu, R. & Balzan, S. Classes of lipid mediators and their effects on vascular inflammation in atherosclerosis. Int. J. Mol. Sci. 24, 1637 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bazan, H. A. et al. Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease. Prostaglandins Leukot. Essent. Fat. Acids 125, 43–47 (2017).

    Article  CAS  Google Scholar 

  116. Elajami, T. K. et al. Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. FASEB J. 30, 2792–2801 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Fredman, G. et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun. 7, 12859 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 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 

  119. Viola, J. R. et al. Resolving lipid mediators maresin 1 and resolvin D2 prevent atheroprogression in mice. Circ. Res. 119, 1030–1038 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. Chiang, N., Dalli, J., Colas, R. A. & Serhan, C. N. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J. Exp. Med. 212, 1203–1217 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chiurchiu, V. et al. Resolution of inflammation is altered in chronic heart failure and entails a dysfunctional responsiveness of T lymphocytes. FASEB J. 33, 909–916 (2019).

    Article  CAS  PubMed  Google Scholar 

  122. Arnardottir, H. et al. The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection. J. Clin. Invest. 131, e142883 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kraft, J. D. et al. Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis. FASEB J. 36, e22173 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. 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 

  125. Hasturk, H. et al. Resolvin E1 (RvE1) attenuates atherosclerotic plaque formation in diet and inflammation-induced atherogenesis. Arterioscler. Thromb. Vasc. Biol. 35, 1123–1133 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Smole, U. et al. Serum amyloid A is a soluble pattern recognition receptor that drives type 2 immunity. Nat. Immunol. 21, 756–765 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wantha, S. et al. Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ. Res. 112, 792–801 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Petri, M. H. et al. The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability. Cardiovasc. Res. 105, 65–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Petri, M. H. et al. Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E-/- mice. Br. J. Pharmacol. 174, 4043–4054 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Laguna-Fernandez, A. et al. ERV1/chemR23 signaling protects against atherosclerosis by modifying oxidized low-density lipoprotein uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. van der Vorst, E. P. C. et al. Hematopoietic chemR23 (chemerin receptor 23) fuels atherosclerosis by sustaining an M1 macrophage-phenotype and guidance of plasmacytoid dendritic cells to murine lesions-brief report. Arterioscler. Thromb. Vasc. Biol. 39, 685–693 (2019).

    Article  PubMed  Google Scholar 

  132. Arita, M. et al. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol. 178, 3912–3917 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Heller, E. A. et al. Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation 112, 578–586 (2005).

    Article  PubMed  Google Scholar 

  134. Park, J., Langmead, C. J. & Riddy, D. M. New advances in targeting the resolution of inflammation: implications for specialized pro-resolving mediator GPCR drug discovery. ACS Pharmacol. Transl. Sci. 3, 88–106 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Panezai, J. & Van Dyke, T. E. Resolution of inflammation: intervention strategies and future applications. Toxicol. Appl. Pharmacol. 449, 116089 (2022).

    Article  CAS  PubMed  Google Scholar 

  136. Ouyang, W. & O’Garra, A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity 50, 871–891 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Mallat, Z. et al. Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler. Thromb. Vasc. Biol. 19, 611–616 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Orecchioni, M. et al. Deleting interleukin-10 from myeloid cells exacerbates atherosclerosis in Apoe-/- mice. Cell Mol. Life Sci. 80, 10 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Caligiuri, G. et al. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol. Med. 9, 10–17 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Han, X. & Boisvert, W. A. Interleukin-10 protects against atherosclerosis by modulating multiple atherogenic macrophage function. Thromb. Haemost. 113, 505–512 (2015).

    Article  PubMed  Google Scholar 

  141. Han, X., Kitamoto, S., Wang, H. & Boisvert, W. A. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB J. 24, 2869–2880 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Pinderski, L. J. et al. Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and macrophage phenotypes. Circ. Res. 90, 1064–1071 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Shi, H. et al. CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis. Front. Immunol. 13, 999470 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kamaly, N. et al. Targeted interleukin-10 nanotherapeutics developed with a microfluidic chip enhance resolution of inflammation in advanced atherosclerosis. ACS Nano 10, 5280–5292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Li, J. et al. Anti-inflammatory cytokine IL10 loaded cRGD liposomes for the targeted treatment of atherosclerosis. J. Microencapsul. 38, 357–364 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Distasio, N., Dierick, F., Ebrahimian, T., Tabrizian, M. & Lehoux, S. Design and development of Branched Poly(β-aminoester) nanoparticles for Interleukin-10 gene delivery in a mouse model of atherosclerosis. Acta Biomater. 143, 356–371 (2022).

    Article  CAS  PubMed  Google Scholar 

  147. Bu, T. et al. Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment. Theranostics 11, 9988–10000 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gao, M. et al. Modulating plaque inflammation via targeted mRNA nanoparticles for the treatment of atherosclerosis. ACS Nano 17, 17721–17739 (2023).

    Article  CAS  PubMed  Google Scholar 

  149. Barcelos, A. L. V. et al. Association of IL-10 to coronary disease severity in patients with metabolic syndrome. Clin. Chim. Acta 495, 394–398 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Goldwater, D., Karlamangla, A., Merkin, S. S., Watson, K. & Seeman, T. Interleukin-10 as a predictor of major adverse cardiovascular events in a racially and ethnically diverse population: Multi-Ethnic Study of Atherosclerosis. Ann. Epidemiol. 30, 9–14.e11 (2019).

    Article  PubMed  Google Scholar 

  151. Wang, X., Wong, K., Ouyang, W. & Rutz, S. Targeting IL-10 family cytokines for the treatment of human diseases. Cold Spring Harb. Perspect. Biol. 11, a028548 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Georgiev, P., Charbonnier, L. M. & Chatila, T. A. Regulatory T cells: the many faces of Foxp3. J. Clin. Immunol. 39, 623–640 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Roncarolo, M. G. & Gregori, S. Is FOXP3 a bona fide marker for human regulatory T cells? Eur. J. Immunol. 38, 925–927 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. Klingenberg, R. et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J. Clin. Invest. 123, 1323–1334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Maganto-Garcia, E., Tarrio, M. L., Grabie, N., Bu, D. X. & Lichtman, A. H. Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. Circulation 124, 185–195 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Proto, J. D. et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity 49, 666–677.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  157. Kasahara, K. et al. Depletion of Foxp3+ regulatory T cells augments CD4+ T cell immune responses in atherosclerosis-prone hypercholesterolemic mice. Heliyon 8, e09981 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Joller, N. et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40, 569–581 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ke, F. et al. Germinal center B cells that acquire nuclear proteins are specifically suppressed by follicular regulatory T cells. eLife 12, e83908 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Chinen, T. et al. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17, 1322–1333 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).

    Article  CAS  PubMed  Google Scholar 

  162. Xue-Mei, L. et al. Changes in CD4+CD25+ Tregs in the pathogenesis of atherosclerosis in ApoE-/- mice. Exp. Biol. Med. 242, 918–925 (2017).

    Article  CAS  Google Scholar 

  163. Shao, Y. et al. IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms. JCI Insight 6, e152511 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Forteza, M. J. et al. Activation of the regulatory T-cell/indoleamine 2,3-dioxygenase axis reduces vascular inflammation and atherosclerosis in hyperlipidemic mice. Front. Immunol. 9, 950 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Ait-Oufella, H. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med. 12, 178–180 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Weber, C. et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J. Clin. Invest. 121, 2898–2910 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sharma, M. et al. Regulatory T cells license macrophage pro-resolving functions during atherosclerosis regression. Circ. Res. 127, 335–353 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Butcher, M. J. et al. Atherosclerosis-driven Treg plasticity results in formation of a dysfunctional subset of plastic IFNγ+ Th1/Tregs. Circ. Res. 119, 1190–1203 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhu, Z. F. et al. Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study. PLoS One 9, e88775 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Döring, Y. et al. Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis. Nat. Cardiovasc. Res. 3, 221–242 (2024).

    Article  Google Scholar 

  171. Weaver, C. T., Elson, C. O., Fouser, L. A. & Kolls, J. K. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu. Rev. Pathol. 8, 477–512 (2013).

    Article  CAS  PubMed  Google Scholar 

  172. Saigusa, R., Winkels, H. & Ley, K. T cell subsets and functions in atherosclerosis. Nat. Rev. Cardiol. 17, 387–401 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Liu, Z. D. et al. Increased Th17 cell frequency concomitant with decreased Foxp3+ Treg cell frequency in the peripheral circulation of patients with carotid artery plaques. Inflamm. Res. 61, 1155–1165 (2012).

    Article  CAS  PubMed  Google Scholar 

  174. Li, Q., Wang, Y., Li, H., Shen, G. & Hu, S. Ox-LDL influences peripheral Th17/Treg balance by modulating Treg apoptosis and Th17 proliferation in atherosclerotic cerebral infarction. Cell Physiol. Biochem. 33, 1849–1862 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Tian, Y. et al. Pioglitazone stabilizes atherosclerotic plaque by regulating the Th17/Treg balance in AMPK-dependent mechanisms. Cardiovasc. Diabetol. 16, 140 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Huang, Y. et al. Interleukin-12p35 deficiency reverses the Th1/Th2 imbalance, aggravates the Th17/Treg imbalance, and ameliorates atherosclerosis in ApoE-/- mice. Mediators Inflamm. 2019, 3152040 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Fan, Q. et al. Anti-atherosclerosis effect of Angong Niuhuang pill via regulating Th17/Treg immune balance and inhibiting chronic inflammatory on ApoE-/- mice model of early and mid-term atherosclerosis. Front. Pharmacol. 10, 1584 (2019).

    Article  CAS  PubMed  Google Scholar 

  178. Rohm, I. et al. Decreased regulatory T cells in vulnerable atherosclerotic lesions: imbalance between pro- and anti-inflammatory cells in atherosclerosis. Mediators Inflamm. 2015, 364710 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  179. George, J. et al. Regulatory T cells and IL-10 levels are reduced in patients with vulnerable coronary plaques. Atherosclerosis 222, 519–523 (2012).

    Article  CAS  PubMed  Google Scholar 

  180. Dietel, B. et al. Decreased numbers of regulatory T cells are associated with human atherosclerotic lesion vulnerability and inversely correlate with infiltrated mature dendritic cells. Atherosclerosis 230, 92–99 (2013).

    Article  CAS  PubMed  Google Scholar 

  181. Herbin, O. et al. Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 32, 605–612 (2012).

    Article  CAS  PubMed  Google Scholar 

  182. Kimura, T. et al. Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B. Circulation 138, 1130–1143 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Wigren, M. et al. Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J. Intern. Med. 269, 546–556 (2011).

    Article  CAS  PubMed  Google Scholar 

  184. Wolf, D. et al. Pathogenic autoimmunity in atherosclerosis evolves from initially protective apolipoprotein B(100)-reactive CD4+ T-regulatory cells. Circulation 142, 1279–1293 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Saigusa, R. et al. Single cell transcriptomics and TCR reconstruction reveal CD4 T cell response to MHC-II-restricted APOB epitope in human cardiovascular disease. Nat. Cardiovasc. Res. 1, 462–475 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Hermansson, A. et al. Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation 123, 1083–1091 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Lu, X. et al. Impact of multiple antigenic epitopes from ApoB100, hHSP60 and Chlamydophila pneumoniae on atherosclerotic lesion development in Apobtm2SgyLdlrtm1HerJ mice. Atherosclerosis 225, 56–68 (2012).

    Article  CAS  PubMed  Google Scholar 

  188. van Puijvelde, G. H. et al. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 114, 1968–1976 (2006).

    Article  PubMed  Google Scholar 

  189. Zhong, Y. et al. CD4+LAP+ and CD4+CD25+Foxp3+ regulatory T cells induced by nasal oxidized low-density lipoprotein suppress effector T cells response and attenuate atherosclerosis in ApoE-/- mice. J. Clin. Immunol. 32, 1104–1117 (2012).

    Article  CAS  PubMed  Google Scholar 

  190. Steffens, S. et al. Short-term treatment with anti-CD3 antibody reduces the development and progression of atherosclerosis in mice. Circulation 114, 1977–1984 (2006).

    Article  CAS  PubMed  Google Scholar 

  191. Sasaki, N. et al. Oral anti-CD3 antibody treatment induces regulatory T cells and inhibits the development of atherosclerosis in mice. Circulation 120, 1996–2005 (2009).

    Article  CAS  PubMed  Google Scholar 

  192. Kasahara, K. et al. CD3 antibody and IL-2 complex combination therapy inhibits atherosclerosis by augmenting a regulatory immune response. J. Am. Heart Assoc. 3, e000719 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Uchiyama, R. et al. Role of regulatory T cells in atheroprotective effects of granulocyte colony-stimulating factor. J. Mol. Cell Cardiol. 52, 1038–1047 (2012).

    Article  CAS  PubMed  Google Scholar 

  194. Takeda, M. et al. Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions. Arterioscler. Thromb. Vasc. Biol. 30, 2495–2503 (2010).

    Article  CAS  PubMed  Google Scholar 

  195. An, T. et al. sFgl2-Treg positive feedback pathway protects against atherosclerosis. Int. J. Mol. Sci. 24, 2338 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Liu, J. et al. LCK inhibitor attenuates atherosclerosis in ApoE-/- mice via regulating T cell differentiation and reverse cholesterol transport. J. Mol. Cell Cardiol. 139, 87–97 (2020).

    Article  CAS  PubMed  Google Scholar 

  197. Meng, X. et al. Statins induce the accumulation of regulatory T cells in atherosclerotic plaque. Mol. Med. 18, 598–605 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Huang, K. et al. Oral FTY720 administration induces immune tolerance and inhibits early development of atherosclerosis in apolipoprotein E-deficient mice. Int. J. Immunopathol. Pharmacol. 25, 397–406 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Winkels, H. et al. CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice. Eur. Heart J. 38, 3590–3599 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. Webster, K. E. et al. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 206, 751–760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Koreth, J. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055–2066 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011).

    Article  CAS  PubMed  Google Scholar 

  203. Hartemann, A. et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 1, 295–305 (2013).

    Article  CAS  PubMed  Google Scholar 

  204. Dietrich, T. et al. Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells. Atherosclerosis 220, 329–336 (2012).

    Article  CAS  PubMed  Google Scholar 

  205. Dinh, T. N. et al. Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation 126, 1256–1266 (2012).

    Article  CAS  PubMed  Google Scholar 

  206. Bonacina, F. et al. Adoptive transfer of CX3CR1 transduced-T regulatory cells improves homing to the atherosclerotic plaques and dampens atherosclerosis progression. Cardiovasc. Res. 117, 2069–2082 (2021).

    Article  CAS  PubMed  Google Scholar 

  207. 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 

  208. Kelsey, M. D. & Pagidipati, N. J. Should we “RESPECT EPA” more now? EPA and DHA for cardiovascular risk reduction. Curr. Cardiol. Rep. 25, 1601–1609 (2023).

    Article  PubMed  Google Scholar 

  209. Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).

    Article  CAS  PubMed  Google Scholar 

  210. Yokoyama, M. et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 369, 1090–1098 (2007).

    Article  CAS  PubMed  Google Scholar 

  211. Khan, S. U. et al. Effect of omega-3 fatty acids on cardiovascular outcomes: a systematic review and meta-analysis. EClinicalMedicine 38, 100997 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Irfan, A., Haider, S. H., Nasir, A., Larik, M. O. & Naz, T. Assessing the efficacy of omega-3 fatty acids + statins vs. statins only on cardiovascular outcomes: a systematic review and meta-analysis of 40,991 patients. Curr. Probl. Cardiol. 49, 102245 (2024).

    Article  PubMed  Google Scholar 

  213. Bernasconi, A. A., Lavie, C. J., Milani, R. V. & Laukkanen, J. A. Omega-3 benefits remain strong post-strength. Mayo Clin. Proc. 96, 1371–1372 (2021).

    Article  PubMed  Google Scholar 

  214. Hamilton-Craig, C., Kostner, K., Colquhoun, D. & Nicholls, S. J. Omega-3 fatty acids and cardiovascular prevention: is the jury still out? Intern. Med. J. 53, 2330–2335 (2023).

    Article  PubMed  Google Scholar 

  215. Ridker, P. M. et al. Effects of randomized treatment with icosapent ethyl and a mineral oil comparator on interleukin-1β, interleukin-6, C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2: a REDUCE-IT biomarker substudy. Circulation 146, 372–379 (2022).

    Article  CAS  PubMed  Google Scholar 

  216. Muldoon, M. F. et al. Fish oil supplementation does not lower C-reactive protein or interleukin-6 levels in healthy adults. J. Intern. Med. 279, 98–109 (2016).

    Article  CAS  PubMed  Google Scholar 

  217. Souza, P. R. et al. Enriched marine oil supplements increase peripheral blood specialized pro-resolving mediators concentrations and reprogram host immune responses: a randomized double-blind placebo-controlled study. Circ. Res. 126, 75–90 (2020).

    Article  CAS  PubMed  Google Scholar 

  218. Cohen, M. G. et al. Insights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: beyond aspirin and clopidogrel. Thromb. Res. 128, 335–340 (2011).

    Article  CAS  PubMed  Google Scholar 

  219. Handke, J. et al. Presepsin for pre-operative prediction of major adverse cardiovascular events in coronary heart disease patients undergoing noncardiac surgery: post hoc analysis of the Leukocytes and Cardiovascular Peri-operative Events-2 (LeukoCAPE-2) study. Eur. J. Anaesthesiol. 37, 908–919 (2020).

    Article  CAS  PubMed  Google Scholar 

  220. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03939338 (2019).

  221. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05924958 (2023).

  222. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT01183962 (2011).

  223. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04380467 (2020).

  224. Sriranjan, R. et al. Low-dose interleukin 2 for the reduction of vascular inflammation in acute coronary syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial. BMJ Open 12, e062602 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  225. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02846883 (2022).

  226. de Lemos, J. A. et al. Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 107, 690–695 (2003).

    Article  PubMed  Google Scholar 

  227. Katra, P. et al. Plasma levels of CCL21, but not CCL19, independently predict future coronary events in a prospective population-based cohort. Atherosclerosis 366, 1–7 (2023).

    Article  CAS  PubMed  Google Scholar 

  228. Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Zhang, S., Ding, Y., Feng, F. & Gao, Y. The role of blood CXCL12 level in prognosis of coronary artery disease: a meta-analysis. Front. Cardiovasc. Med. 9, 938540 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Sjaarda, J. et al. Blood CSF1 and CXCL12 as causal mediators of coronary artery disease. J. Am. Coll. Cardiol. 72, 300–310 (2018).

    Article  CAS  PubMed  Google Scholar 

  231. Gistera, A., Ketelhuth, D. F. J., Malin, S. G. & Hansson, G. K. Animal models of atherosclerosis-supportive notes and tricks of the trade. Circ. Res. 130, 1869–1887 (2022).

    Article  CAS  PubMed  Google Scholar 

  232. Marquez, A. B., van der Vorst, E. P. C. & Maas, S. L. Key chemokine pathways in atherosclerosis and their therapeutic potential. J. Clin. Med. 10, 3825 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Upadhye, A. et al. Diversification and CXCR4-dependent establishment of the bone marrow B-1a cell pool governs atheroprotective IgM production linked to human coronary atherosclerosis. Circ. Res. 125, e55–e70 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Zernecke, A. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2, ra81 (2009).

    Article  PubMed  Google Scholar 

  235. Wan, W., Lionakis, M. S., Liu, Q., Roffe, E. & Murphy, P. M. Genetic deletion of chemokine receptor Ccr7 exacerbates atherogenesis in ApoE-deficient mice. Cardiovasc. Res. 97, 580–588 (2013).

    Article  CAS  PubMed  Google Scholar 

  236. Luchtefeld, M. et al. Chemokine receptor 7 knockout attenuates atherosclerotic plaque development. Circulation 122, 1621–1628 (2010).

    Article  CAS  PubMed  Google Scholar 

  237. Döring, Y. et al. Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis. Nat. Cardiovasc. Res. 3, 221–242 (2024).

    Article  Google Scholar 

  238. Landsman, L. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113, 963–972 (2009).

    Article  CAS  PubMed  Google Scholar 

  239. White, G. E., McNeill, E., Channon, K. M. & Greaves, D. R. Fractalkine promotes human monocyte survival via a reduction in oxidative stress. Arterioscler. Thromb. Vasc. Biol. 34, 2554–2562 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Rousselle, A. et al. CXCL5 limits macrophage foam cell formation in atherosclerosis. J. Clin. Invest. 123, 1343–1347 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Akhavanpoor, M. et al. CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions. Drug Des. Devel. Ther. 8, 2359–2371 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  242. Godson, C., Guiry, P. & Brennan, E. Lipoxin mimetics and the resolution of inflammation. Annu. Rev. Pharmacol. Toxicol. 63, 429–448 (2023).

    Article  CAS  PubMed  Google Scholar 

  243. Vital, S. A. et al. Formyl-peptide receptor 2/3/lipoxin A4 receptor regulates neutrophil-platelet aggregation and attenuates cerebral inflammation: impact for therapy in cardiovascular disease. Circulation 133, 2169–2179 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Libreros, S. et al. A new E-series resolvin: RvE4 stereochemistry and function in efferocytosis of inflammation-resolution. Front. Immunol. 11, 631319 (2020).

    Article  CAS  PubMed  Google Scholar 

  245. Vidar Hansen, T. & Serhan, C. N. Protectins: their biosynthesis, metabolism and structure-functions. Biochem. Pharmacol. 206, 115330 (2022).

    Article  CAS  PubMed  Google Scholar 

  246. Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Bang, S. et al. GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. J. Clin. Invest. 128, 3568–3582 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  248. Serhan, C. N. et al. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J. Exp. Med. 206, 15–23 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Chiang, N., Libreros, S., Norris, P. C., de la Rosa, X. & Serhan, C. N. Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions. J. Clin. Invest. 129, 5294–5311 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors received support from Deutsche Forschungsgemeinschaft (DFG) (SFB1123-A1/A10 to Y.D. and C.W., and 390857198-EXC 2145 to C.W.), the European Research Council (AdG 692511 to C.W.), the German Ministry of Education and Research (BMBF) and the German Center for Cardiovascular Research (DZHK) (81×2600254, 81Z0600202 and 81Z0600203 to Y.D., C.W. and E.P.C.v.d.V), grants from the Interdisciplinary Center for Clinical Research in the Faculty of Medicine at the RWTH Aachen University (to E.P.C.v.d.V.), and the Swiss National Foundation (SNF) Project (IDs 310030_197655 and 4078P0_198297 to Y.D.). C.W. is van der Laar-Professor of Atherosclerosis.

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Author notes

  1. These authors contributed equally: Yvonne Döring, Emiel P. C. van der Vorst.

Authors and Affiliations

  1. Department of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Yvonne Döring

  2. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany

    Yvonne Döring, Emiel P. C. van der Vorst & Christian Weber

  3. DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

    Yvonne Döring & Christian Weber

  4. Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland

    Yvonne Döring

  5. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany

    Emiel P. C. van der Vorst

  6. Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen, Germany

    Emiel P. C. van der Vorst

  7. Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany

    Emiel P. C. van der Vorst

  8. Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands

    Christian Weber

  9. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Christian Weber

Authors
  1. Yvonne Döring
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  3. Christian Weber
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The authors contributed substantially to all aspects of the article.

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Correspondence to Yvonne Döring, Emiel P. C. van der Vorst or Christian Weber.

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Nature Reviews Cardiology thanks Claudia Monaco; Holger Winkels, who co-reviewed with Jan Wrobel; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Döring, Y., van der Vorst, E.P.C. & Weber, C. Targeting immune cell recruitment in atherosclerosis. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-01023-z

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