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:

Trained immunity in atherosclerotic cardiovascular disease

Nature Reviews Cardiology volume 20, pages 799–811 (2023)Cite this article

Subjects

Abstract

Trained immunity, also known as innate immune memory, is a persistent hyper-responsive functional state of innate immune cells. Accumulating evidence implicates trained immunity as an underlying mechanism of chronic inflammation in atherosclerotic cardiovascular disease. In this context, trained immunity is induced by endogenous atherosclerosis-promoting factors, such as modified lipoproteins or hyperglycaemia, causing broad metabolic and epigenetic reprogramming of the myeloid cell compartment. In addition to traditional cardiovascular risk factors, lifestyle factors, including unhealthy diets, sedentary lifestyle, sleep deprivation and psychosocial stress, as well as inflammatory comorbidities, have been shown to activate trained immunity-like mechanisms in bone marrow haematopoietic stem cells. In this Review, we discuss the molecular and cellular mechanisms of trained immunity, its systemic regulation through haematopoietic progenitor cells in the bone marrow, and the activation of these mechanisms by cardiovascular disease risk factors. We also highlight other trained immunity features that are relevant for atherosclerotic cardiovascular disease, including the diverse cell types that show memory characteristics and transgenerational inheritance of trained immunity traits. Finally, we propose potential strategies for the therapeutic modulation of trained immunity to manage atherosclerotic cardiovascular disease.

Key points

  • Trained immunity denotes the long-term hyperinflammatory functional reprogramming of innate immune cells, which can occur in mature cells and their bone marrow myeloid progenitors.

  • Lifestyle-related factors that promote atherosclerotic cardiovascular disease, including dyslipidaemia, hyperglycaemia, consumption of Western-type diets, obesity, stress and disturbed sleep, have been shown to induce trained immunity in experimental models.

  • Trained immunity is mediated by the activation of intracellular metabolic pathways, including glycolysis, glutaminolysis and mevalonate synthesis, which subsequently induces persistent epigenetic reprogramming of the cell by affecting the activity of epigenetic enzymes.

  • Local histone methylation occurs on genes encoding inflammatory factors, mediated by the action of a class of long non-coding RNAs, called immune gene-priming long non-coding RNAs, that operate within discrete topologically associated domains.

  • We propose trained immunity as a novel framework to understand the role of inflammation in cardiovascular disease pathophysiology, which provides novel pharmacological targets to prevent cardiovascular disease.

  • The key to developing successful treatment strategies focused on trained immunity is to target molecular targets that are specific for trained immunity in specific myeloid cells (or subsets of cells prone to trained immunity) in restricted time windows of trained immunity activation.

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: Trained immunity in atherosclerotic cardiovascular disease.
Fig. 2: Schematic representation of common metabolic and epigenetic pathways driving trained immunity.
Fig. 3: Cells involved in central and peripheral trained immunity relevant for atherosclerosis.

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Nidorf, S. M. et al. Colchicine in patients with chronic coronary disease. N. Engl. J. Med. 383, 1838–1847 (2020).

    CAS  PubMed  Google Scholar 

  3. Tardif, J. C. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 381, 2497–2505 (2019).

    CAS  PubMed  Google Scholar 

  4. Visseren, F. L. J. et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur. Heart J. 42, 3227–3337 (2021).

    PubMed  Google Scholar 

  5. Libby, P. The changing landscape of atherosclerosis. Nature 592, 524–533 (2021).

    CAS  PubMed  Google Scholar 

  6. Boring, L., Gosling, J., Cleary, M. & Charo, I. F. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894–897 (1998).

    CAS  PubMed  Google Scholar 

  7. Bekkering, S. et al. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis 254, 228–236 (2016).

    CAS  PubMed  Google Scholar 

  8. Shirai, T. et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J. Exp. Med. 213, 337–354 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Li, Y. et al. A functional genomics approach to understand variation in cytokine production in humans. Cell 167, 1099–1110.e14 (2016).

    CAS  PubMed  Google Scholar 

  10. Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Dominguez-Andres, J. et al. Trained immunity: adaptation within innate immune mechanisms. Physiol. Rev. 103, 313–346 (2023).

    CAS  PubMed  Google Scholar 

  13. Netea, M. G., Quintin, J. & van der Meer, J. W. Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355–361 (2011).

    CAS  PubMed  Google Scholar 

  14. Fanucchi, S., Dominguez-Andres, J., Joosten, L. A. B., Netea, M. G. & Mhlanga, M. M. The intersection of epigenetics and metabolism in trained immunity. Immunity 54, 32–43 (2021).

    CAS  PubMed  Google Scholar 

  15. Divangahi, M. et al. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat. Immunol. 22, 2–6 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Higgins, J. P. et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 355, i5170 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. Prentice, S. et al. BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial. Lancet Infect. Dis. 21, 993–1003 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lanz-Mendoza, H. & Contreras-Garduno, J. Innate immune memory in invertebrates: concept and potential mechanisms. Dev. Comp. Immunol. 127, 104285 (2022).

    CAS  PubMed  Google Scholar 

  19. Bekkering, S. et al. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler. Thromb. Vasc. Biol. 34, 1731–1738 (2014).

    CAS  PubMed  Google Scholar 

  20. Thiem, K. et al. Hyperglycemic memory of innate immune cells promotes in vitro proinflammatory responses of human monocytes and murine macrophages. J. Immunol. 206, 807–813 (2021).

    CAS  PubMed  Google Scholar 

  21. Edgar, L. et al. Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis. Circulation 144, 961–982 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. van der Heijden, C. et al. Catecholamines induce trained immunity in monocytes in vitro and in vivo. Circ. Res. 127, 269–283 (2020).

    PubMed  Google Scholar 

  23. Li, X. et al. Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities. Cell 185, 1709–1727.e18 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chavakis, T., Wielockx, B. & Hajishengallis, G. Inflammatory modulation of hematopoiesis: linking trained immunity and clonal hematopoiesis with chronic disorders. Annu. Rev. Physiol. 84, 183–207 (2022).

    PubMed  Google Scholar 

  25. Mitroulis, I., Hajishengallis, G. & Chavakis, T. Bone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities. Cardiovasc. Res. https://doi.org/10.1093/cvr/cvad003 (2023).

    Article  PubMed  Google Scholar 

  26. Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190.e19 (2018).

    CAS  PubMed  Google Scholar 

  27. Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–175.e14 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kleinnijenhuis, J. et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. USA 109, 17537–17542 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).

    CAS  PubMed  Google Scholar 

  30. Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    PubMed  PubMed Central  Google Scholar 

  31. Keating, S. T. et al. Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein. J. Mol. Med. 98, 819–831 (2020).

    CAS  PubMed  Google Scholar 

  32. Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    PubMed  PubMed Central  Google Scholar 

  34. Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bekkering, S. et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell 172, 135–146.e9 (2018).

    CAS  PubMed  Google Scholar 

  36. Keating, S. T. et al. The Set7 lysine methyltransferase regulates plasticity in oxidative phosphorylation necessary for trained immunity induced by β-glucan. Cell Rep. 31, 107548 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Groh, L. A. et al. oxLDL-induced trained immunity is dependent on mitochondrial metabolic reprogramming. Immunometabolism 3, e210025 (2021).

    PubMed  PubMed Central  Google Scholar 

  38. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. Novakovic, B. et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368.e14 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fok, E. T., Davignon, L., Fanucchi, S. & Mhlanga, M. M. The lncRNA connection between cellular metabolism and epigenetics in trained immunity. Front. Immunol. 9, 3184 (2018).

    CAS  PubMed  Google Scholar 

  41. Fanucchi, S. et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat. Genet. 51, 138–150 (2019).

    CAS  PubMed  Google Scholar 

  42. Mourits, V. P. et al. Lysine methyltransferase G9a is an important modulator of trained immunity. Clin. Transl. Immunol. 10, e1253 (2021).

    CAS  Google Scholar 

  43. Moorlag, S. et al. An integrative genomics approach identifies KDM4 as a modulator of trained immunity. Eur. J. Immunol. 52, 431–446 (2022).

    CAS  PubMed  Google Scholar 

  44. Bannister, S. et al. Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes. Sci. Adv. 8, eabn4002 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Verma, D. et al. Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects. Sci. Rep. 7, 12305 (2017).

    PubMed  PubMed Central  Google Scholar 

  46. Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. McAlpine, C. S. et al. Sleep modulates haematopoiesis and protects against atherosclerosis. Nature 566, 383–387 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Frodermann, V. et al. Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells. Nat. Med. 25, 1761–1771 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Noz, M. et al. Reprogramming of bone marrow myeloid progenitor cells in patients with severe coronary artery disease. eLife 9, e60939 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yusuf, S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364, 937–952 (2004).

    PubMed  Google Scholar 

  51. Bekkering, S. et al. In vitro experimental model of trained innate immunity in human primary monocytes. Clin. Vaccin. Immunol. 23, 926–933 (2016).

    CAS  Google Scholar 

  52. van der Valk, F. M. et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 134, 611–624 (2016).

    PubMed  PubMed Central  Google Scholar 

  53. Bekkering, S. et al. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metab. 30, 1–2 (2019).

    CAS  PubMed  Google Scholar 

  54. Cosentino, F. et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 41, 255–323 (2020).

    PubMed  Google Scholar 

  55. Miao, F. et al. Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes 63, 1748–1762 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. van der Heijden, C. et al. Aldosterone induces trained immunity: the role of fatty acid synthesis. Cardiovasc. Res. 116, 317–328 (2020).

    PubMed  Google Scholar 

  57. van der Heijden, C. et al. Arterial wall inflammation and increased hematopoietic activity in patients with primary aldosteronism. J. Clin. Endocrinol. Metab. 105, e1967–e1980 (2020).

    PubMed  Google Scholar 

  58. NCD Risk Factor Collaboration (NCD-RisC).Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet 390, 2627–2642 (2017).

    PubMed Central  Google Scholar 

  59. Schloss, M. J., Swirski, F. K. & Nahrendorf, M. Modifiable cardiovascular risk, hematopoiesis, and innate immunity. Circ. Res. 126, 1242–1259 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Christ, A., Lauterbach, M. & Latz, E. Western diet and the immune system: an inflammatory connection. Immunity 51, 794–811 (2019).

    CAS  PubMed  Google Scholar 

  61. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    CAS  PubMed  Google Scholar 

  62. Fuke, N., Nagata, N., Suganuma, H. & Ota, T. Regulation of gut microbiota and metabolic endotoxemia with dietary factors.Nutrients 11, 2277 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Lopez-Garcia, E. et al. Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction. Am. J. Clin. Nutr. 80, 1029–1035 (2004).

    CAS  PubMed  Google Scholar 

  64. van Kampen, E., Jaminon, A., van Berkel, T. J. & Van Eck, M. Diet-induced (epigenetic) changes in bone marrow augment atherosclerosis. J. Leukoc. Biol. 96, 833–841 (2014).

    PubMed  Google Scholar 

  65. Ifrim, D. C. et al. Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin. Vaccin. Immunol. 21, 534–545 (2014).

    Google Scholar 

  66. Geng, S. et al. The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis. Nat. Commun. 7, 13436 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Temba, G. S. et al. Urban living in healthy Tanzanians is associated with an inflammatory status driven by dietary and metabolic changes. Nat. Immunol. 22, 287–300 (2021).

    CAS  PubMed  Google Scholar 

  68. Hata, M. et al. Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation. Science 379, 45–62 (2023).

    CAS  PubMed  Google Scholar 

  69. Dimsdale, J. E. Psychological stress and cardiovascular disease. J. Am. Coll. Cardiol. 51, 1237–1246 (2008).

    PubMed  PubMed Central  Google Scholar 

  70. Powell, N. D. et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc. Natl Acad. Sci. USA 110, 16574–16579 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Poller, W. C. et al. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 607, 578–584 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Barrett, T. J. et al. Chronic stress primes innate immune responses in mice and humans. Cell Rep. 36, 109595 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cappuccio, F. P., Cooper, D., D’Elia, L., Strazzullo, P. & Miller, M. A. Sleep duration predicts cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. Eur. Heart J. 32, 1484–1492 (2011).

    PubMed  Google Scholar 

  74. Vallat, R., Shah, V. D., Redline, S., Attia, P. & Walker, M. P. Broken sleep predicts hardened blood vessels. PLoS Biol. 18, e3000726 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. McAlpine, C. S. et al. Sleep exerts lasting effects on hematopoietic stem cell function and diversity.J. Exp. Med. 219, e20220081 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Noz, M. P. et al. Sixteen-week physical activity intervention in subjects with increased cardiometabolic risk shifts innate immune function towards a less proinflammatory state. J. Am. Heart Assoc. 8, e013764 (2019).

    PubMed  PubMed Central  Google Scholar 

  77. Leentjens, J. et al. Trained innate immunity as a novel mechanism linking infection and the development of atherosclerosis. Circ. Res. 122, 664–669 (2018).

    CAS  PubMed  Google Scholar 

  78. Arts, R. J. W., Joosten, L. A. B. & Netea, M. G. The potential role of trained immunity in autoimmune and autoinflammatory disorders. Front. Immunol. 9, 298 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. Badii, M. et al. Urate-induced epigenetic modifications in myeloid cells. Arthritis Res. Ther. 23, 202 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Neidhart, M. et al. Oligomeric S100A4 is associated with monocyte innate immune memory and bypass of tolerance to subsequent stimulation with lipopolysaccharides. Front. Immunol. 10, 791 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Noz, M. P. et al. An explorative study on monocyte reprogramming in the context of periodontitis in vitro and in vivo. Front. Immunol. 12, 695227 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Crisan, T. O. et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann. Rheum. Dis. 75, 755–762 (2016).

    CAS  PubMed  Google Scholar 

  83. Zhang, B. et al. Single-cell RNA sequencing reveals induction of distinct trained-immunity programs in human monocytes.J. Clin. Invest. 137, e147719 (2022).

    Google Scholar 

  84. Yao, Y. et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175, 1634–1650.e17 (2018).

    CAS  PubMed  Google Scholar 

  85. Mitroulis, I., Hajishengallis, G. & Chavakis, T. Trained immunity and cardiometabolic disease: the role of bone marrow. Arterioscler. Thromb. Vasc. Biol. 41, 48–54 (2021).

    CAS  PubMed  Google Scholar 

  86. Moorlag, S. et al. BCG vaccination induces long-term functional reprogramming of human neutrophils. Cell Rep. 33, 108387 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161.e12 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Cirovic, B. et al. BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment. Cell Host Microbe 28, 322–334 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Hole, C. R. et al. Induction of memory-like dendritic cell responses in vivo. Nat. Commun. 10, 2955 (2019).

    PubMed  PubMed Central  Google Scholar 

  90. Kleinnijenhuis, J. et al. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin. Immunol. 155, 213–219 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Schnack, L. et al. Mechanisms of trained innate immunity in oxLDL primed human coronary smooth muscle cells. Front. Immunol. 10, 13 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sohrabi, Y. et al. OxLDL-mediated immunologic memory in endothelial cells. J. Mol. Cell Cardiol. 146, 121–132 (2020).

    CAS  PubMed  Google Scholar 

  93. Kalafati, L., Hatzioannou, A., Hajishengallis, G. & Chavakis, T. The role of neutrophils in trained immunity. Immunol. Rev. 314, 142–157 (2023).

    CAS  PubMed  Google Scholar 

  94. Silvestre-Roig, C., Braster, Q., Ortega-Gomez, A. & Soehnlein, O. Neutrophils as regulators of cardiovascular inflammation. Nat. Rev. Cardiol. 17, 327–340 (2020).

    PubMed  Google Scholar 

  95. El-Osta, A. et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 205, 2409–2417 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Okabe, J. et al. Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells. Circ. Res. 110, 1067–1076 (2012).

    CAS  PubMed  Google Scholar 

  97. Katzmarski, N. et al. Transmission of trained immunity and heterologous resistance to infections across generations. Nat. Immunol. 22, 1382–1390 (2021).

    CAS  PubMed  Google Scholar 

  98. Kaufmann, E. et al. Lack of evidence for intergenerational inheritance of immune resistance to infections. Nat. Immunol. 23, 203–207 (2022).

    CAS  PubMed  Google Scholar 

  99. Berendsen, M. et al. Parental Bacillus Calmette-Guerin vaccine scars decrease infant mortality in the first six weeks of life: a retrospective cohort study. EClinicalMedicine 39, 101049 (2021).

    PubMed  PubMed Central  Google Scholar 

  100. Schulz, L. C. The Dutch Hunger Winter and the developmental origins of health and disease. Proc. Natl Acad. Sci. USA 107, 16757–16758 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Mulder, W. J. M., Ochando, J., Joosten, L. A. B., Fayad, Z. A. & Netea, M. G. Therapeutic targeting of trained immunity. Nat. Rev. Drug Discov. 18, 553–566 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Lawler, P. R. et al. Targeting cardiovascular inflammation: next steps in clinical translation. Eur. Heart J. 42, 113–131 (2021).

    CAS  PubMed  Google Scholar 

  104. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Courties, G. et al. Ischemic stroke activates hematopoietic bone marrow stem cells. Circ. Res. 116, 407–417 (2015).

    CAS  PubMed  Google Scholar 

  106. van Leent, M. M. T. et al. Regulating trained immunity with nanomedicine. Nat. Rev. Mater. 7, 465–481 (2022).

    Google Scholar 

  107. Mulder, W. J. M. et al. High-density lipoprotein nanobiologics for precision medicine. Acc. Chem. Res. 51, 127–137 (2018).

    CAS  PubMed  Google Scholar 

  108. van Leent, M. M. T. et al. A modular approach toward producing nanotherapeutics targeting the innate immune system. Sci. Adv. 7, eabe7853 (2021).

    PubMed  PubMed Central  Google Scholar 

  109. Duivenvoorden, R. et al. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat. Commun. 5, 3065 (2014).

    PubMed  Google Scholar 

  110. Tang, J. et al. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.Sci Adv. 1, e1400223 (2015).

    PubMed  PubMed Central  Google Scholar 

  111. Binderup, T. et al. Imaging-assisted nanoimmunotherapy for atherosclerosis in multiple species. Sci. Transl. Med. 11, eaaw7736 (2019).

    PubMed  PubMed Central  Google Scholar 

  112. van Leent, M. M. T. et al. Prosaposin mediates inflammation in atherosclerosis. Sci. Transl. Med. 13, eabe1433 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kleinnijenhuis, J. et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J. Innate Immun. 6, 152–158 (2014).

    CAS  PubMed  Google Scholar 

  114. Moore, K. J. & Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341–355 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Stiekema, L. C. A. et al. Impact of cholesterol on proinflammatory monocyte production by the bone marrow. Eur. Heart J. 42, 4309–4320 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Seijkens, T. et al. Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis. FASEB J. 28, 2202–2213 (2014).

    CAS  PubMed  Google Scholar 

  117. Noye, E. C. et al. Postnatal inflammation in ApoE-/- mice is associated with immune training and atherosclerosis. Clin. Sci. 135, 1859–1871 (2021).

    CAS  Google Scholar 

  118. Bekkering, S. et al. Postnatal inflammation following intrauterine inflammation exacerbates the development of atherosclerosis in ApoE-/- mice. Clin. Sci. 133, 1185–1196 (2019).

    CAS  Google Scholar 

  119. Huijser, E. et al. Trained immunity in primary Sjogren’s syndrome: linking type I interferons to a pro-atherogenic phenotype. Front. Immunol. 13, 840751 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Mylona, E. E. et al. Enhanced interleukin-1β production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals. Arthritis Res. Ther. 14, R158 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

N.P.R. and M.G.N. were supported by a CVON grant of the Dutch Heart Foundation (IN CONTROL II; CVON2018-27). N.P.R. was supported by a grant of the ERA-CVD Joint Transnational Call 2018, which is supported by the Dutch Heart Foundation in the Hague (JTC2018, project MEMORY; 2018T093). M.G.N. is supported by an ERC Advanced Grant (FP/2007-2013/ERC grant 2012-322698) and a Spinoza Prize (NWO SPI 92-266). S.B. is supported by the Dutch Heart Foundation (2018T028). W.J.M. is supported by an ERC Advanced grant (TOLERANCE) and an NWO Vici grant. Figures for initial submission were created with BioRender.com.

Author information

Authors and Affiliations

  1. Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

    Niels P. Riksen, Siroon Bekkering, Willem J. M. Mulder & Mihai G. Netea

  2. Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands

    Willem J. M. Mulder

  3. Department for Genomics and Immunoregulation, University of Bonn, Bonn, Germany

    Mihai G. Netea

Authors
  1. Niels P. Riksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Siroon Bekkering
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Willem J. M. Mulder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mihai G. Netea
    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 Niels P. Riksen.

Ethics declarations

Competing interests

M.G.N. and W.J.M. are scientific cofounders of and have equity in Trained Therapeutix Discovery and are scientific founders of BioTRIP. M.G.N. is scientific founder of Lemba. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cardiology thanks Ziad Mallat and the other, anonymous, reviewer(s) 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

Riksen, N.P., Bekkering, S., Mulder, W.J.M. et al. Trained immunity in atherosclerotic cardiovascular disease. Nat Rev Cardiol 20, 799–811 (2023). https://doi.org/10.1038/s41569-023-00894-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-023-00894-y

This article is cited by

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