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  • Review Article
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Neutrophils as regulators of cardiovascular inflammation

Nature Reviews Cardiology volume 17, pages 327–340 (2020)Cite this article

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Abstract

Neutrophils have traditionally been viewed as bystanders or biomarkers of cardiovascular disease. However, studies in the past decade have demonstrated the important functions of neutrophils during cardiovascular inflammation and repair. In this Review, we discuss the influence of traditional and novel cardiovascular risk factors on neutrophil production and function. We then appraise the current knowledge of the contribution of neutrophils to the different stages of atherosclerosis, including atherogenesis, plaque destabilization and plaque erosion. In the context of cardiovascular complications of atherosclerosis, we highlight the dichotomous role of neutrophils in pathogenic and repair processes in stroke, heart failure, myocardial infarction and neointima formation. Finally, we emphasize how detailed knowledge of neutrophil functions in cardiovascular homeostasis and disease can be used to generate therapeutic strategies to target neutrophil numbers, functional status and effector mechanisms.

Key points

  • Hypercholesterolaemia and hyperglycaemia heighten neutrophil production in the bone marrow and at extramedullary sites, thereby accelerating cardiovascular inflammation.

  • Lifestyle factors, including stress, disturbed sleep and nutrition, influence cardiovascular inflammation in part by altering neutrophil production in the bone marrow.

  • Neutrophils accelerate all stages of atherosclerosis by fostering monocyte recruitment and macrophage activation and through cytotoxicity.

  • During complications of cardiovascular inflammation, such as neointima formation and myocardial infarction, neutrophils have reparative functions primarily by promoting endothelial regrowth and angiogenesis.

  • In cardiac hypertrophy and stroke, neutrophil-driven macrophage activation and stimulation of coagulation have a negative effect.

  • Time-specific and site-specific interference with neutrophil recruitment to large arteries and inhibition of neutrophil extracellular trap discharge or neutralization of active components of neutrophil extracellular traps are important targets to reduce cardiovascular inflammation.

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Fig. 1: Risk factor–neutrophil interaction network.
Fig. 2: Stage-dependent contribution of neutrophils to atherosclerosis.
Fig. 3: Neutrophils in cardiovascular complications.

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References

  1. Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Swirski, F. K. & Nahrendorf, M. Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat. Rev. Immunol. 18, 733–744 (2018).

    CAS  PubMed  Google Scholar 

  3. Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagonists and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248–261 (2017).

    CAS  PubMed  Google Scholar 

  4. Casanova-Acebes, M. et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153, 1025–1035 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Tak, T., Tesselaar, K., Pillay, J., Borghans, J. A. & Koenderman, L. What’s your age again? Determination of human neutrophil half-lives revisited. J. Leukoc. Biol. 94, 595–601 (2013).

    CAS  PubMed  Google Scholar 

  6. Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Pillay, J. et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 116, 625–627 (2010).

    CAS  PubMed  Google Scholar 

  8. Lahoz-Beneytez, J. et al. Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives. Blood 127, 3431–3438 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hidalgo, A., Chilvers, E. R., Summers, C. & Koenderman, L. The neutrophil life cycle. Trends Immunol. 40, 584–597 (2019).

    CAS  PubMed  Google Scholar 

  10. Lok, L. S. C. et al. Phenotypically distinct neutrophils patrol uninfected human and mouse lymph nodes. Proc. Natl Acad. Sci. USA 116, 19083–19089 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Walmsley, S. R. et al. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J. Exp. Med. 201, 105–115 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. van Raam, B. J., Drewniak, A., Groenewold, V., van den Berg, T. K. & Kuijpers, T. W. Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3. Blood 112, 2046–2054 (2008).

    PubMed  PubMed Central  Google Scholar 

  13. Matsushima, H. et al. Neutrophil differentiation into a unique hybrid population exhibiting dual phenotype and functionality of neutrophils and dendritic cells. Blood 121, 1677–1689 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lindemans, C. A. et al. Respiratory syncytial virus inhibits granulocyte apoptosis through a phosphatidylinositol 3-kinase and NF-kappaB-dependent mechanism. J. Immunol. 176, 5529–5537 (2006).

    CAS  PubMed  Google Scholar 

  15. Casanova-Acebes, M. et al. Neutrophils instruct homeostatic and pathological states in naive tissues. J. Exp. Med. 215, 2778–2795 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Maas, S. L., Soehnlein, O. & Viola, J. R. Organ-specific mechanisms of transendothelial neutrophil migration in the lung, liver, kidney, and aorta. Front. Immunol. 9, 2739 (2018).

    PubMed  PubMed Central  Google Scholar 

  17. Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat. Immunol. 12, 761–769 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, J. et al. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 358, 111–116 (2017).

    CAS  PubMed  Google Scholar 

  19. Chen, L. et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell 167, 1398–1414 e1324 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Xie, X. et al. Single-cell transcriptome profiling reveals neutrophil heterogeneity and orchestrated maturation during homeostasis and bacterial infection. Preprint at bioRxiv https://doi.org/10.1101/792200 (2019).

    Article  Google Scholar 

  21. Pedersen, C. C. et al. Changes in gene expression during G-CSF-induced emergency granulopoiesis in humans. J. Immunol. 197, 1989–1999 (2016).

    CAS  PubMed  Google Scholar 

  22. Naranbhai, V. et al. Genomic modulators of gene expression in human neutrophils. Nat. Commun. 6, 7545 (2015).

    PubMed  Google Scholar 

  23. de Kleijn, S. et al. Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia. PLoS One 7, e38255 (2012).

    PubMed  PubMed Central  Google Scholar 

  24. Fischer, J. et al. Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils. Nat. Immunol. 20, 546–558 (2019).

    CAS  PubMed  Google Scholar 

  25. Cassatella, M. A., Ostberg, N. K., Tamassia, N. & Soehnlein, O. Biological roles of neutrophil-derived granule proteins and cytokines. Trends Immunol. 40, 648–664 (2019).

    CAS  PubMed  Google Scholar 

  26. Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Westerterp, M. et al. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways. Cell Stem Cell 11, 195–206 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gu, Q. et al. AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science 363, 1085–1088 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Takubo, K. et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nagareddy, P. R. et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 17, 695–708 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Sarrazy, V. et al. Disruption of Glut1 in hematopoietic stem cells prevents myelopoiesis and enhanced glucose flux in atheromatous plaques of ApoE−/− mice. Circ. Res. 118, 1062–1077 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kraakman, M. J. et al. Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. J. Clin. Invest. 127, 2133–2147 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. Tyrkalska, S. D. et al. Inflammasome regulates hematopoiesis through cleavage of the master erythroid transcription factor GATA1. Immunity 51, 50–63 e55 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pietras, E. M. et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat. Cell Biol. 18, 607–618 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161 e112 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Westerterp, M. et al. Cholesterol efflux pathways suppress inflammasome activation, NETosis, and atherogenesis. Circulation 138, 898–912 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Dorsheimer, L. et al. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 4, 25–33 (2019).

    PubMed  Google Scholar 

  39. 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 

  40. 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 

  41. Sano, S. et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1beta/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71, 875–886 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang, W. et al. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 (V617F) mice. Circ. Res. 123, e35–e47 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl Med. 10, eaan8292 (2018).

    PubMed  PubMed Central  Google Scholar 

  44. Arnett, D. K. et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the american college of cardiology/american heart association task force on clinical practice guidelines. J. Am. Coll. Cardiol. 74, e177–e232 (2019).

    PubMed  PubMed Central  Google Scholar 

  45. Rosengren, A. et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 364, 953–962 (2004).

    PubMed  Google Scholar 

  46. Kivimaki, M. & Steptoe, A. Effects of stress on the development and progression of cardiovascular disease. Nat. Rev. Cardiol. 15, 215–229 (2018).

    CAS  PubMed  Google Scholar 

  47. Remch, M., Laskaris, Z., Flory, J., Mora-McLaughlin, C. & Morabia, A. Post-traumatic stress disorder and cardiovascular diseases: a cohort study of men and women involved in cleaning the debris of the world trade center complex. Circ. Cardiovasc. Qual. Outcomes 11, e004572 (2018).

    PubMed  PubMed Central  Google Scholar 

  48. Song, H. et al. Stress related disorders and risk of cardiovascular disease: population based, sibling controlled cohort study. Br. Med. J. 365, l1255 (2019).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Tawakol, A. et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet 389, 834–845 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. McKim, D. B. et al. Social stress mobilizes hematopoietic stem cells to establish persistent splenic myelopoiesis. Cell Rep. 25, 2552–2562 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Chevre, R., Silvestre-Roig, C. & Soehnlein, O. Nutritional modulation of innate immunity: the fat-bile-gut connection. Trends Endocrinol. Metab. 29, 686–698 (2018).

    CAS  PubMed  Google Scholar 

  55. Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 8, 845 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. Komaroff, A. L. The microbiome and risk for obesity and diabetes. JAMA 317, 355–356 (2017).

    PubMed  Google Scholar 

  57. Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Schiattarella, G. G. et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur. Heart J. 38, 2948–2956 (2017).

    CAS  PubMed  Google Scholar 

  59. Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Koeth, R. A. et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Brandsma, E. et al. A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circ. Res. 124, 94–100 (2019).

    CAS  PubMed  Google Scholar 

  62. Kain, V. et al. Obesogenic diet in aging mice disrupts gut microbe composition and alters neutrophil:lymphocyte ratio, leading to inflamed milieu in acute heart failure. FASEB J. 33, 6456–6469 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Benakis, C. et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells. Nat. Med. 22, 516–523 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Adrover, J. M. et al. A neutrophil timer coordinates immune defense and vascular protection. Immunity 50, 390–402 (2019).

    CAS  PubMed  Google Scholar 

  65. Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. GBD 2017 Global Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736–1788 (2018).

    Google Scholar 

  67. Ortega-Gomez, A. et al. Cathepsin G controls arterial but not venular myeloid cell recruitment. Circulation 134, 1176–1188 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Drechsler, M., Megens, R. T., van Zandvoort, M., Weber, C. & Soehnlein, O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 122, 1837–1845 (2010).

    CAS  PubMed  Google Scholar 

  69. Mure, L. S. et al. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science 359, eaao0318 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  71. de Juan, A. et al. Artery-associated sympathetic innervation drives rhythmic vascular inflammation of arteries and veins. Circulation 140, 1100–1114 (2019).

    PubMed  PubMed Central  Google Scholar 

  72. Ionita, M. G. et al. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler. Thromb. Vasc. Biol. 30, 1842–1848 (2010).

    CAS  PubMed  Google Scholar 

  73. Moreno, P. R., Purushothaman, K. R., Sirol, M., Levy, A. P. & Fuster, V. Neovascularization in human atherosclerosis. Circulation 113, 2245–2252 (2006).

    PubMed  Google Scholar 

  74. Soehnlein, O. et al. Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol. Med. 5, 471–481 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Chevre, R. et al. High-resolution imaging of intravascular atherogenic inflammation in live mice. Circ. Res. 114, 770–779 (2014).

    CAS  PubMed  Google Scholar 

  76. Eriksson, E. E. Intravital microscopy on atherosclerosis in apolipoprotein e-deficient mice establishes microvessels as major entry pathways for leukocytes to advanced lesions. Circulation 124, 2129–2138 (2011).

    CAS  PubMed  Google Scholar 

  77. Massena, S. et al. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood 126, 2016–2026 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ferraro, B. et al. Pro-angiogenic macrophage phenotype to promote myocardial repair. J. Am. Coll. Cardiol. 73, 2990–3002 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  81. Friedman, G. D., Klatsky, A. L. & Siegelaub, A. B. The leukocyte count as a predictor of myocardial infarction. N. Engl. J. Med. 290, 1275–1278 (1974).

    CAS  PubMed  Google Scholar 

  82. Guasti, L. et al. Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularisation. A systematic review on more than 34,000 subjects. Thromb. Haemost. 106, 591–599 (2011).

    CAS  PubMed  Google Scholar 

  83. Soehnlein, O., Lindbom, L. & Weber, C. Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood 114, 4613–4623 (2009).

    CAS  PubMed  Google Scholar 

  84. Doring, Y. et al. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ. Res. 110, 1052–1056 (2012).

    PubMed  Google Scholar 

  85. 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).

    PubMed  Google Scholar 

  86. Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O. & Lindbom, L. Heparinoid sevuparin inhibits Streptococcus-induced vascular leak through neutralizing neutrophil-derived proteins. FASEB J. 33, 10443–10452 (2019).

    CAS  PubMed  Google Scholar 

  87. Delporte, C. et al. Impact of myeloperoxidase-LDL interactions on enzyme activity and subsequent posttranslational oxidative modifications of apoB-100. J. Lipid Res. 55, 747–757 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Soehnlein, O. et al. Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages. J. Clin. Invest. 118, 3491–3502 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu, Y. et al. Myeloid-specific deletion of peptidylarginine deiminase 4 mitigates atherosclerosis. Front. Immunol. 9, 1680 (2018).

    PubMed  PubMed Central  Google Scholar 

  90. Knight, J. S. et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ. Res. 114, 947–956 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Doring, Y. et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 125, 1673–1683 (2012).

    PubMed  Google Scholar 

  92. Warnatsch, A., Ioannou, M., Wang, Q. & Papayannopoulos, V. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349, 316–320 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Soehnlein, O., Ortega-Gomez, A., Doring, Y. & Weber, C. Neutrophil-macrophage interplay in atherosclerosis: protease-mediated cytokine processing versus NET release. Thromb. Haemost. 114, 866–867 (2015).

    PubMed  Google Scholar 

  94. Libby, P., Pasterkamp, G., Crea, F. & Jang, I. K. Reassessing the mechanisms of acute coronary syndromes. Circ. Res. 124, 150–160 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Paulin, N. et al. Double-strand DNA sensing Aim2 inflammasome regulates atherosclerotic plaque vulnerability. Circulation 138, 321–323 (2018).

    PubMed  Google Scholar 

  97. Musher, D. M., Abers, M. S. & Corrales-Medina, V. F. Acute infection and myocardial infarction. N. Engl. J. Med. 380, 171–176 (2019).

    CAS  PubMed  Google Scholar 

  98. Mawhin, M. A. et al. Neutrophils recruited by leukotriene B4 induce features of plaque destabilization during endotoxaemia. Cardiovasc. Res. 114, 1656–1666 (2018).

    CAS  PubMed  Google Scholar 

  99. Pasterkamp, G., den Ruijter, H. M. & Libby, P. Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease. Nat. Rev. Cardiol. 14, 21–29 (2017).

    CAS  PubMed  Google Scholar 

  100. Quillard, T. et al. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur. Heart J. 36, 1394–1404 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Franck, G. et al. Flow perturbation mediates neutrophil recruitment and potentiates endothelial injury via TLR2 in mice: implications for superficial erosion. Circ. Res. 121, 31–42 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Franck, G. et al. Roles of PAD4 and NETosis in experimental atherosclerosis and arterial injury: implications for superficial erosion. Circ. Res. 123, 33–42 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Rhys, H. I. et al. Neutrophil microvesicles from healthy control and rheumatoid arthritis patients prevent the inflammatory activation of macrophages. EBioMedicine 29, 60–69 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).

    CAS  PubMed  Google Scholar 

  105. Hristov, M. et al. Importance of CXC chemokine receptor 2 in the homing of human peripheral blood endothelial progenitor cells to sites of arterial injury. Circ. Res. 100, 590–597 (2007).

    CAS  PubMed  Google Scholar 

  106. Romson, J. L. et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67, 1016–1023 (1983).

    CAS  PubMed  Google Scholar 

  107. Schloss, M. J. et al. The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment. EMBO Mol. Med. 8, 937–948 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lorchner, H. et al. Myocardial healing requires Reg3beta-dependent accumulation of macrophages in the ischemic heart. Nat. Med. 21, 353–362 (2015).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  110. Wang, Y. et al. Wnt5a-mediated neutrophil recruitment has an obligatory role in pressure overload-induced cardiac dysfunction. Circulation 140, 487–499 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Soehnlein, O. et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 112, 1461–1471 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Patel, B. et al. CCR2+ monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload. JACC Basic. Transl Sci. 3, 230–244 (2018).

    PubMed  PubMed Central  Google Scholar 

  113. Wang, L. et al. CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration. Eur. Heart J. 39, 1818–1831 (2018).

    CAS  PubMed  Google Scholar 

  114. Hermann, D. M. & Gunzer, M. Polymorphonuclear neutrophils play a decisive role for brain injury and neurological recovery poststroke. Stroke 50, e40–e41 (2019).

    PubMed  Google Scholar 

  115. Herz, J. et al. Role of neutrophils in exacerbation of brain injury after focal cerebral ischemia in hyperlipidemic mice. Stroke 46, 2916–2925 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Neumann, J. et al. Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J. Neurosci. 28, 5965–5975 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang, J. et al. Prognostic role of neutrophil-lymphocyte ratio in patients with acute ischemic stroke. Medicine 96, e8624 (2017).

    PubMed  PubMed Central  Google Scholar 

  118. Gaertner, F. & Massberg, S. Blood coagulation in immunothrombosis-at the frontline of intravascular immunity. Semin. Immunol. 28, 561–569 (2016).

    CAS  PubMed  Google Scholar 

  119. Pircher, J. et al. Cathelicidins prime platelets to mediate arterial thrombosis and tissue inflammation. Nat. Commun. 9, 1523 (2018).

    PubMed  PubMed Central  Google Scholar 

  120. Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).

    CAS  PubMed  Google Scholar 

  121. Ducroux, C. et al. Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke. Stroke 49, 754–757 (2018).

    PubMed  Google Scholar 

  122. De Meyer, S. F., Suidan, G. L., Fuchs, T. A., Monestier, M. & Wagner, D. D. Extracellular chromatin is an important mediator of ischemic stroke in mice. Arterioscler. Thromb. Vasc. Biol. 32, 1884–1891 (2012).

    PubMed  PubMed Central  Google Scholar 

  123. Allen, C. et al. Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with decondensed DNA. J. Immunol. 189, 381–392 (2012).

    CAS  PubMed  Google Scholar 

  124. Braunersreuther, V. et al. Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice. J. Mol. Cell Cardiol. 48, 789–798 (2010).

    CAS  PubMed  Google Scholar 

  125. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03402815?term=NCT03402815&rank=1 (2018).

  126. European Medicines Agency. EU Clinical Trial Register. EMA https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-000775-24/GB (2016).

  127. Schall, T. J. & Proudfoot, A. E. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat. Rev. Immunol. 11, 355–363 (2011).

    CAS  PubMed  Google Scholar 

  128. Sager, H. B. et al. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci. Transl Med. 8, 342ra380 (2016).

    Google Scholar 

  129. Kempf, T. et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat. Med. 17, 581–588 (2011).

    CAS  PubMed  Google Scholar 

  130. Drechsler, M. et al. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ. Res. 116, 827–835 (2015).

    CAS  PubMed  Google Scholar 

  131. Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Rossaint, J. et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 123, 2573–2584 (2014).

    CAS  PubMed  Google Scholar 

  133. Stark, K. et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 128, 2435–2449 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).

    CAS  PubMed  Google Scholar 

  135. Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Wang, Z., Li, J., Cho, J. & Malik, A. B. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nat. Nanotechnol. 9, 204–210 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Miettinen, H. M., Gripentrog, J. M., Lord, C. I. & Nagy, J. O. CD177-mediated nanoparticle targeting of human and mouse neutrophils. PLoS One 13, e0200444 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. Silvestre-Roig, C., Fridlender, Z. G., Glogauer, M. & Scapini, P. Neutrophil diversity in health and disease. Trends Immunol. 40, 565–583 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhu, Y. P. et al. Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow. Cell Rep. 24, 2329–2341 e2328 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Evrard, M. et al. Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions. Immunity 48, 364–379 e368 (2018).

    CAS  PubMed  Google Scholar 

  141. Cuartero, M. I. et al. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARgamma agonist rosiglitazone. Stroke 44, 3498–3508 (2013).

    CAS  PubMed  Google Scholar 

  142. Zhao, X. et al. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage. Nat. Commun. 8, 602 (2017).

    PubMed  PubMed Central  Google Scholar 

  143. Carlucci, P. M. et al. Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus. JCI Insight 3, e99276 (2018).

    PubMed Central  Google Scholar 

  144. Teague, H. L. et al. Neutrophil subsets, platelets, and vascular disease in psoriasis. JACC Basic. Transl Sci. 4, 1–14 (2019).

    PubMed  PubMed Central  Google Scholar 

  145. Zhao, D., Liu, J., Xie, W. & Qi, Y. Cardiovascular risk assessment: a global perspective. Nat. Rev. Cardiol. 12, 301–311 (2015).

    PubMed  Google Scholar 

  146. Andersson, C., Johnson, A. D., Benjamin, E. J., Levy, D. & Vasan, R. S. 70-year legacy of the Framingham heart study. Nat. Rev. Cardiol. 16, 687–698 (2019).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  148. Svensson, E. C. et al. TET2-driven clonal hematopoiesis predicts enhanced response to canakinumab in the CANTOS trial: an exploratory analysis [abstract]. Circulation 138, 15111 (2018).

    Google Scholar 

  149. Baldus, S. et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 108, 1440–1445 (2003).

    CAS  PubMed  Google Scholar 

  150. Zhang, R. et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 286, 2136–2142 (2001).

    CAS  PubMed  Google Scholar 

  151. Borissoff, J. I. et al. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler. Thromb. Vasc. Biol. 33, 2032–2040 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Schuster, M. et al. Surveillance of myelodysplastic syndrome via migration analyses of blood neutrophils: a potential prognostic tool. J. Immunol. 201, 3546–3557 (2018).

    CAS  PubMed  Google Scholar 

  153. Eulenberg-Gustavus, C., Bahring, S., Maass, P. G., Luft, F. C. & Kettritz, R. Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets. J. Exp. Med. 214, 2089–2101 (2017).

    PubMed  PubMed Central  Google Scholar 

  154. Hasenberg, A. et al. Catchup: a mouse model for imaging-based tracking and modulation of neutrophil granulocytes. Nat. Methods 12, 445–452 (2015).

    CAS  PubMed  Google Scholar 

  155. Devi, S. et al. Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow. J. Exp. Med. 210, 2321–2336 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Jung, K. et al. Endoscopic time-lapse imaging of immune cells in infarcted mouse hearts. Circ. Res. 112, 891–899 (2013).

    CAS  PubMed  Google Scholar 

  157. Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 164, 325 (2016).

    CAS  PubMed  Google Scholar 

  159. Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661–1674 (2018).

    CAS  PubMed  Google Scholar 

  160. Fernandez, D. M. et al. Single-cell immune landscape of human atherosclerotic plaques. Nat. Med. 25, 1576–1588 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Winkels, H. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ. Res. 122, 1675–1688 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Wirka, R. C. et al. Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat. Med. 25, 1280–1289 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors receive funding from the Deutsche Forschungsgemeinschaft (SO876/11-1, SFB914 TP B8, SFB1123 TP A6 and TP B5, OR465/1-1), the Vetenskapsrådet (2017-01762), the Else-Kröner-Fresenius Stiftung and the Leducq Foundation.

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Authors and Affiliations

  1. Institute for Cardiovascular Prevention (IPEK), Klinikum LMU Munich, Munich, Germany

    Carlos Silvestre-Roig, Quinte Braster, Almudena Ortega-Gomez & Oliver Soehnlein

  2. German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany

    Carlos Silvestre-Roig, Quinte Braster, Almudena Ortega-Gomez & Oliver Soehnlein

  3. Department of Physiology and Pharmacology (FyFa), Karolinska Institute, Stockholm, Sweden

    Oliver Soehnlein

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All authors contributed equally to all aspects of the article.

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Correspondence to Oliver Soehnlein.

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Competing interests

C.S.-R. holds a patent on targeting histones in cardiovascular inflammation. O.S. has consulted for Novo Nordisk and AstraZeneca, has received a grant from Novo Nordisk to study the effect of circadian rhythms on atherosclerosis and holds a patent on targeting histones in cardiovascular inflammation. Q.B. and A.O.-G declare no competing interests.

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Glossary

Granulopoiesis

Production of granulocytes, including eosinophils, basophils and neutrophils; comprises the differentiation process from the haematopoietic stem cell into the mature cell.

Epigenome

The profile of chemical changes in the DNA and associated histones of an organism.

Myelopoiesis

Production of myeloid cells, including eosinophils, basophils, neutrophils and monocytes.

Trained immunity

Immune memory of the innate immune system, involving epigenetic programming of myeloid cells enabling a stronger immune response to secondary stimuli.

Clonal haematopoiesis of indeterminate potential

(CHIP). Clonal expansion of blood cells as a result of somatic mutations in genes that confer a growth advantage to haematopoietic stem cells.

Extramedullary haematopoiesis

Production of blood cells outside the bone marrow; for example, in the spleen.

Angiogenesis

Formation of blood vessels from pre-existing vessels.

Microvesicles

Also known as microparticles. Type of extracellular vesicles of approximately 50–1,000 nm in diameter that are released from the plasma membrane of cells.

Neointima

Type of scar tissue in blood vessels formed as a consequence of a surgical intervention, such as angioplasty or stent placement.

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Silvestre-Roig, C., Braster, Q., Ortega-Gomez, A. et al. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol 17, 327–340 (2020). https://doi.org/10.1038/s41569-019-0326-7

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