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.
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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Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).
Swirski, F. K. & Nahrendorf, M. Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat. Rev. Immunol. 18, 733–744 (2018).
Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagonists and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248–261 (2017).
Casanova-Acebes, M. et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153, 1025–1035 (2013).
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).
Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).
Pillay, J. et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 116, 625–627 (2010).
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).
Hidalgo, A., Chilvers, E. R., Summers, C. & Koenderman, L. The neutrophil life cycle. Trends Immunol. 40, 584–597 (2019).
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).
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).
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).
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).
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).
Casanova-Acebes, M. et al. Neutrophils instruct homeostatic and pathological states in naive tissues. J. Exp. Med. 215, 2778–2795 (2018).
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).
Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat. Immunol. 12, 761–769 (2011).
Wang, J. et al. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 358, 111–116 (2017).
Chen, L. et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell 167, 1398–1414 e1324 (2016).
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).
Pedersen, C. C. et al. Changes in gene expression during G-CSF-induced emergency granulopoiesis in humans. J. Immunol. 197, 1989–1999 (2016).
Naranbhai, V. et al. Genomic modulators of gene expression in human neutrophils. Nat. Commun. 6, 7545 (2015).
de Kleijn, S. et al. Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia. PLoS One 7, e38255 (2012).
Fischer, J. et al. Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils. Nat. Immunol. 20, 546–558 (2019).
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).
Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010).
Westerterp, M. et al. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways. Cell Stem Cell 11, 195–206 (2012).
Gu, Q. et al. AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science 363, 1085–1088 (2019).
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).
Nagareddy, P. R. et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 17, 695–708 (2013).
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).
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).
Tyrkalska, S. D. et al. Inflammasome regulates hematopoiesis through cleavage of the master erythroid transcription factor GATA1. Immunity 51, 50–63 e55 (2019).
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).
Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161 e112 (2018).
Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–175 (2018).
Westerterp, M. et al. Cholesterol efflux pathways suppress inflammasome activation, NETosis, and atherogenesis. Circulation 138, 898–912 (2018).
Dorsheimer, L. et al. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 4, 25–33 (2019).
Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).
Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).
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).
Wang, W. et al. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 (V617F) mice. Circ. Res. 123, e35–e47 (2018).
Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl Med. 10, eaan8292 (2018).
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).
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).
Kivimaki, M. & Steptoe, A. Effects of stress on the development and progression of cardiovascular disease. Nat. Rev. Cardiol. 15, 215–229 (2018).
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).
Song, H. et al. Stress related disorders and risk of cardiovascular disease: population based, sibling controlled cohort study. Br. Med. J. 365, l1255 (2019).
Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014).
Tawakol, A. et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet 389, 834–845 (2017).
McKim, D. B. et al. Social stress mobilizes hematopoietic stem cells to establish persistent splenic myelopoiesis. Cell Rep. 25, 2552–2562 (2018).
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).
McAlpine, C. S. et al. Sleep modulates haematopoiesis and protects against atherosclerosis. Nature 566, 383–387 (2019).
Chevre, R., Silvestre-Roig, C. & Soehnlein, O. Nutritional modulation of innate immunity: the fat-bile-gut connection. Trends Endocrinol. Metab. 29, 686–698 (2018).
Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 8, 845 (2017).
Komaroff, A. L. The microbiome and risk for obesity and diabetes. JAMA 317, 355–356 (2017).
Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).
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).
Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016).
Koeth, R. A. et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).
Brandsma, E. et al. A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circ. Res. 124, 94–100 (2019).
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).
Benakis, C. et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells. Nat. Med. 22, 516–523 (2016).
Adrover, J. M. et al. A neutrophil timer coordinates immune defense and vascular protection. Immunity 50, 390–402 (2019).
Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).
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).
Ortega-Gomez, A. et al. Cathepsin G controls arterial but not venular myeloid cell recruitment. Circulation 134, 1176–1188 (2016).
Drechsler, M., Megens, R. T., van Zandvoort, M., Weber, C. & Soehnlein, O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 122, 1837–1845 (2010).
Mure, L. S. et al. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science 359, eaao0318 (2018).
Winter, C. et al. Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell Metab. 28, 175–182 (2018).
de Juan, A. et al. Artery-associated sympathetic innervation drives rhythmic vascular inflammation of arteries and veins. Circulation 140, 1100–1114 (2019).
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).
Moreno, P. R., Purushothaman, K. R., Sirol, M., Levy, A. P. & Fuster, V. Neovascularization in human atherosclerosis. Circulation 113, 2245–2252 (2006).
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).
Chevre, R. et al. High-resolution imaging of intravascular atherogenic inflammation in live mice. Circ. Res. 114, 770–779 (2014).
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).
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).
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).
Ferraro, B. et al. Pro-angiogenic macrophage phenotype to promote myocardial repair. J. Am. Coll. Cardiol. 73, 2990–3002 (2019).
Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).
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).
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).
Soehnlein, O., Lindbom, L. & Weber, C. Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood 114, 4613–4623 (2009).
Doring, Y. et al. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ. Res. 110, 1052–1056 (2012).
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).
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).
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).
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).
Liu, Y. et al. Myeloid-specific deletion of peptidylarginine deiminase 4 mitigates atherosclerosis. Front. Immunol. 9, 1680 (2018).
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).
Doring, Y. et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 125, 1673–1683 (2012).
Warnatsch, A., Ioannou, M., Wang, Q. & Papayannopoulos, V. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349, 316–320 (2015).
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).
Libby, P., Pasterkamp, G., Crea, F. & Jang, I. K. Reassessing the mechanisms of acute coronary syndromes. Circ. Res. 124, 150–160 (2019).
Silvestre-Roig, C. et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature 569, 236–240 (2019).
Paulin, N. et al. Double-strand DNA sensing Aim2 inflammasome regulates atherosclerotic plaque vulnerability. Circulation 138, 321–323 (2018).
Musher, D. M., Abers, M. S. & Corrales-Medina, V. F. Acute infection and myocardial infarction. N. Engl. J. Med. 380, 171–176 (2019).
Mawhin, M. A. et al. Neutrophils recruited by leukotriene B4 induce features of plaque destabilization during endotoxaemia. Cardiovasc. Res. 114, 1656–1666 (2018).
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).
Quillard, T. et al. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur. Heart J. 36, 1394–1404 (2015).
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).
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).
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).
Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).
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).
Romson, J. L. et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67, 1016–1023 (1983).
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).
Lorchner, H. et al. Myocardial healing requires Reg3beta-dependent accumulation of macrophages in the ischemic heart. Nat. Med. 21, 353–362 (2015).
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).
Wang, Y. et al. Wnt5a-mediated neutrophil recruitment has an obligatory role in pressure overload-induced cardiac dysfunction. Circulation 140, 487–499 (2019).
Soehnlein, O. et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 112, 1461–1471 (2008).
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).
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).
Hermann, D. M. & Gunzer, M. Polymorphonuclear neutrophils play a decisive role for brain injury and neurological recovery poststroke. Stroke 50, e40–e41 (2019).
Herz, J. et al. Role of neutrophils in exacerbation of brain injury after focal cerebral ischemia in hyperlipidemic mice. Stroke 46, 2916–2925 (2015).
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).
Zhang, J. et al. Prognostic role of neutrophil-lymphocyte ratio in patients with acute ischemic stroke. Medicine 96, e8624 (2017).
Gaertner, F. & Massberg, S. Blood coagulation in immunothrombosis-at the frontline of intravascular immunity. Semin. Immunol. 28, 561–569 (2016).
Pircher, J. et al. Cathelicidins prime platelets to mediate arterial thrombosis and tissue inflammation. Nat. Commun. 9, 1523 (2018).
Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).
Ducroux, C. et al. Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke. Stroke 49, 754–757 (2018).
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).
Allen, C. et al. Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with decondensed DNA. J. Immunol. 189, 381–392 (2012).
Braunersreuther, V. et al. Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice. J. Mol. Cell Cardiol. 48, 789–798 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03402815?term=NCT03402815&rank=1 (2018).
European Medicines Agency. EU Clinical Trial Register. EMA https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-000775-24/GB (2016).
Schall, T. J. & Proudfoot, A. E. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat. Rev. Immunol. 11, 355–363 (2011).
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).
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).
Drechsler, M. et al. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ. Res. 116, 827–835 (2015).
Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).
Rossaint, J. et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 123, 2573–2584 (2014).
Stark, K. et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 128, 2435–2449 (2016).
Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).
Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).
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).
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).
Silvestre-Roig, C., Fridlender, Z. G., Glogauer, M. & Scapini, P. Neutrophil diversity in health and disease. Trends Immunol. 40, 565–583 (2019).
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).
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).
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).
Zhao, X. et al. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage. Nat. Commun. 8, 602 (2017).
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).
Teague, H. L. et al. Neutrophil subsets, platelets, and vascular disease in psoriasis. JACC Basic. Transl Sci. 4, 1–14 (2019).
Zhao, D., Liu, J., Xie, W. & Qi, Y. Cardiovascular risk assessment: a global perspective. Nat. Rev. Cardiol. 12, 301–311 (2015).
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).
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
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).
Baldus, S. et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 108, 1440–1445 (2003).
Zhang, R. et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 286, 2136–2142 (2001).
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).
Schuster, M. et al. Surveillance of myelodysplastic syndrome via migration analyses of blood neutrophils: a potential prognostic tool. J. Immunol. 201, 3546–3557 (2018).
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).
Hasenberg, A. et al. Catchup: a mouse model for imaging-based tracking and modulation of neutrophil granulocytes. Nat. Methods 12, 445–452 (2015).
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).
Jung, K. et al. Endoscopic time-lapse imaging of immune cells in infarcted mouse hearts. Circ. Res. 112, 891–899 (2013).
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).
Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 164, 325 (2016).
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).
Fernandez, D. M. et al. Single-cell immune landscape of human atherosclerotic plaques. Nat. Med. 25, 1576–1588 (2019).
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).
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).
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.
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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Production of granulocytes, including eosinophils, basophils and neutrophils; comprises the differentiation process from the haematopoietic stem cell into the mature cell.
The profile of chemical changes in the DNA and associated histones of an organism.
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.
Formation of blood vessels from pre-existing vessels.
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.
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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