Download PDF
Thromb Haemost 2019; 119(04): 542-552
DOI: 10.1055/s-0039-1678664
Theme Issue Article
Georg Thieme Verlag KG Stuttgart · New York

Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation

Kristof Van Avondt
1   Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany
,
Lars Maegdefessel
2   Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
3   Molecular Vascular Medicine Group, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
4   DZHK, Partner Site Munich Heart Alliance, Munich, Germany
,
Oliver Soehnlein
1   Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany
4   DZHK, Partner Site Munich Heart Alliance, Munich, Germany
5   Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden
6   Department of Medicine, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations Funding The authors are supported by the DFG (SFB914 TP B08, SFB1123 TP A06 & B05, SO876/6–1, SO876/11–1), the German Center for Cardiovascular Research (DZHK), the Fritz Thyssen Foundation, the Leducq foundation, the Else Kröner Fresenius Stiftung, the Vetenskapsrådet (2017–01762), the FöFoLe program of the LMU Munich and the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 675111.
Further Information

Publication History

01 October 2018

09 December 2018

Publication Date:
07 February 2019 (online)

Also available at
   Permissions and Reprints

Abstract

Neutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.

Keywords

neutrophil - NETosis - atherogenic inflammation - atherothrombotic disease
 

  • References

  • 1 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17 (11) 1410-1422
    CrossrefPubMedGoogle Scholar
  • 2 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12 (03) 204-212
    CrossrefPubMedGoogle Scholar
  • 3 Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol 2015; 15 (02) 104-116
    CrossrefPubMedGoogle Scholar
  • 4 Yvan-Charvet L, Welch C, Pagler TA. , et al. Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation 2008; 118 (18) 1837-1847
    CrossrefPubMedGoogle Scholar
  • 5 Westerterp M, Murphy AJ, Wang M. , et al. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ Res 2013; 112 (11) 1456-1465
    CrossrefPubMedGoogle Scholar
  • 6 Ridker PM, Everett BM, Thuren T. , et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
    CrossrefPubMedGoogle Scholar
  • 7 Drechsler M, Megens RTA, van Zandvoort M, Weber C, Soehnlein O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010; 122 (18) 1837-1845
    CrossrefPubMedGoogle Scholar
  • 8 Westerterp M, Fotakis P, Ouimet M. , et al. Cholesterol efflux pathways suppress inflammasome activation, NETosis, and atherogenesis. Circulation 2018; 138 (09) 898-912
    CrossrefPubMedGoogle Scholar
  • 9 Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 2005; 22 (03) 285-294
    CrossrefPubMedGoogle Scholar
  • 10 Murphy AJ, Akhtari M, Tolani S. , et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest 2011; 121 (10) 4138-4149
    CrossrefPubMedGoogle Scholar
  • 11 Yvan-Charvet L, Pagler T, Gautier EL. , et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 2010; 328 (5986): 1689-1693
    CrossrefPubMedGoogle Scholar
  • 12 Wang M, Subramanian M, Abramowicz S. , et al. Interleukin-3/granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion, monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency. Arterioscler Thromb Vasc Biol 2014; 34 (05) 976-984
    CrossrefPubMedGoogle Scholar
  • 13 Christopher MJ, Link DC. Regulation of neutrophil homeostasis. Curr Opin Hematol 2007; 14 (01) 3-8
    CrossrefPubMedGoogle Scholar
  • 14 Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest 2010; 120 (07) 2423-2431
    CrossrefPubMedGoogle Scholar
  • 15 Megens RTA, Vijayan S, Lievens D. , et al. Presence of luminal neutrophil extracellular traps in atherosclerosis. Thromb Haemost 2012; 107 (03) 597-598
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Chèvre R, González-Granado JM, Megens RTA. , et al. High-resolution imaging of intravascular atherogenic inflammation in live mice. Circ Res 2014; 114 (05) 770-779
    CrossrefPubMedGoogle Scholar
  • 17 van Leeuwen M, Gijbels MJJ, Duijvestijn A. , et al. Accumulation of myeloperoxidase-positive neutrophils in atherosclerotic lesions in LDLR-/- mice. Arterioscler Thromb Vasc Biol 2008; 28 (01) 84-89
    CrossrefPubMedGoogle Scholar
  • 18 Rotzius P, Thams S, Soehnlein O. , et al. Distinct infiltration of neutrophils in lesion shoulders in ApoE-/- mice. Am J Pathol 2010; 177 (01) 493-500
    CrossrefPubMedGoogle Scholar
  • 19 Zernecke A, Bot I, Djalali-Talab Y. , et al. Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res 2008; 102 (02) 209-217
    CrossrefPubMedGoogle Scholar
  • 20 Naruko T, Ueda M, Haze K. , et al. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 2002; 106 (23) 2894-2900
    CrossrefPubMedGoogle Scholar
  • 21 Tavora FR, Ripple M, Li L, Burke AP. Monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques. BMC Cardiovasc Disord 2009; 9: 27
    CrossrefPubMedGoogle Scholar
  • 22 Paul VSV, Paul CMP, Kuruvilla S. Quantification of various inflammatory cells in advanced atherosclerotic plaques. J Clin Diagn Res 2016; 10 (05) EC35-EC38
    PubMedGoogle Scholar
  • 23 van der Wal AC, Becker AE. Atherosclerotic plaque rupture—pathologic basis of plaque stability and instability. Cardiovasc Res 1999; 41 (02) 334-344
    CrossrefPubMedGoogle Scholar
  • 24 Pertiwi KR, van der Wal AC, Pabittei DR. , et al. Neutrophil extracellular traps participate in all different types of thrombotic and haemorrhagic complications of coronary atherosclerosis. Thromb Haemost 2018; 118 (06) 1078-1087
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Ionita MG, van den Borne P, Catanzariti LM. , et al. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler Thromb Vasc Biol 2010; 30 (09) 1842-1848
    CrossrefPubMedGoogle Scholar
  • 26 Quillard T, Araújo HA, Franck G, Shvartz E, Sukhova G, Libby P. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 2015; 36 (22) 1394-1404
    CrossrefPubMedGoogle Scholar
  • 27 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473 (7347): 317-325
    CrossrefPubMedGoogle Scholar
  • 28 Horne BD, Anderson JL, John JM. , et al; Intermountain Heart Collaborative Study Group. Which white blood cell subtypes predict increased cardiovascular risk?. J Am Coll Cardiol 2005; 45 (10) 1638-1643
    CrossrefPubMedGoogle Scholar
  • 29 Coller BS. Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene?. Arterioscler Thromb Vasc Biol 2005; 25 (04) 658-670
    CrossrefPubMedGoogle Scholar
  • 30 Pende A, Artom N, Bertolotto M, Montecucco F, Dallegri F. Role of neutrophils in atherogenesis: an update. Eur J Clin Invest 2016; 46 (03) 252-263
    CrossrefPubMedGoogle Scholar
  • 31 Borregaard N. Neutrophils, from marrow to microbes. Immunity 2010; 33 (05) 657-670
    CrossrefPubMedGoogle Scholar
  • 32 Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11 (08) 519-531
    CrossrefPubMedGoogle Scholar
  • 33 Soehnlein O, Kai-Larsen Y, Frithiof R. , et al. Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages. J Clin Invest 2008; 118 (10) 3491-3502
    CrossrefPubMedGoogle Scholar
  • 34 Soehnlein O, Steffens S, Hidalgo A, Weber C. Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol 2017; 17 (04) 248-261
    CrossrefPubMedGoogle Scholar
  • 35 Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nature Reviews Immunology [Internet]; 2017 . Available at: http://www.nature.com/doifinder/10.1038/nri.2017.105. Accessed December 7, 2017
    PubMedGoogle Scholar
  • 36 Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med 2017; 23 (03) 279-287
    CrossrefPubMedGoogle Scholar
  • 37 Van Avondt K, Hartl D. Mechanisms and disease relevance of neutrophil extracellular trap formation. Eur J Clin Invest 2018; 48 (Suppl. 02) e12919
    CrossrefPubMedGoogle Scholar
  • 38 Mangold A, Alias S, Scherz T. , et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res 2015; 116 (07) 1182-1192
    CrossrefPubMedGoogle Scholar
  • 39 Stakos DA, Kambas K, Konstantinidis T. , et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 2015; 36 (22) 1405-1414
    CrossrefPubMedGoogle Scholar
  • 40 Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 2015; 349 (6245): 316-320
    CrossrefPubMedGoogle Scholar
  • 41 Knight JS, Luo W, O'Dell AA. , et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ Res 2014; 114 (06) 947-956
    CrossrefPubMedGoogle Scholar
  • 42 Liu Y, Carmona-Rivera C, Moore E. , et al. Myeloid-specific deletion of peptidylarginine deiminase 4 mitigates atherosclerosis. Front Immunol 2018; 9: 1680
    CrossrefPubMedGoogle Scholar
  • 43 Franck G, Mawson TL, Folco EJ. , et al. Roles of PAD4 and NETosis in experimental atherosclerosis and arterial injury: implications for superficial erosion. Circ Res 2018; 123 (01) 33-42
    CrossrefPubMedGoogle Scholar
  • 44 Döring Y, Soehnlein O, Weber C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ Res 2017; 120 (04) 736-743
    CrossrefPubMedGoogle Scholar
  • 45 Brinkmann V, Reichard U, Goosmann C. , et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663): 1532-1535
    CrossrefPubMedGoogle Scholar
  • 46 Fuchs TA, Abed U, Goosmann C. , et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176 (02) 231-241
    CrossrefPubMedGoogle Scholar
  • 47 Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010; 191 (03) 677-691
    CrossrefPubMedGoogle Scholar
  • 48 Pilsczek FH, Salina D, Poon KKH. , et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 2010; 185 (12) 7413-7425
    CrossrefPubMedGoogle Scholar
  • 49 Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ 2009; 16 (11) 1438-1444
    CrossrefPubMedGoogle Scholar
  • 50 Yipp BG, Petri B, Salina D. , et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012; 18 (09) 1386-1393
    CrossrefPubMedGoogle Scholar
  • 51 Xu J, Zhang X, Pelayo R. , et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15 (11) 1318-1321
    CrossrefPubMedGoogle Scholar
  • 52 Awasthi D, Nagarkoti S, Kumar A. , et al. Oxidized LDL induced extracellular trap formation in human neutrophils via TLR-PKC-IRAK-MAPK and NADPH-oxidase activation. Free Radic Biol Med 2016; 93: 190-203
    CrossrefPubMedGoogle Scholar
  • 53 Wang Y, Wang W, Wang N, Tall AR, Tabas I. Mitochondrial oxidative stress promotes atherosclerosis and neutrophil extracellular traps in aged mice. Arterioscler Thromb Vasc Biol 2017; 37 (08) e99-e107
    PubMedGoogle Scholar
  • 54 Massberg S, Grahl L, von Bruehl M-L. , et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (08) 887-896
    CrossrefPubMedGoogle Scholar
  • 55 Clark SR, Ma AC, Tavener SA. , et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13 (04) 463-469
    CrossrefPubMedGoogle Scholar
  • 56 Maugeri N, Campana L, Gavina M. , et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost 2014; 12 (12) 2074-2088
    CrossrefPubMedGoogle Scholar
  • 57 Sreeramkumar V, Adrover JM, Ballesteros I. , et al. Neutrophils scan for activated platelets to initiate inflammation. Science 2014; 346 (6214): 1234-1238
    CrossrefPubMedGoogle Scholar
  • 58 Rossaint J, Herter JM, Van Aken H. , et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 2014; 123 (16) 2573-2584
    CrossrefPubMedGoogle Scholar
  • 59 Vajen T, Koenen RR, Werner I. , et al. Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis. Sci Rep 2018; 8 (01) 10647
    CrossrefPubMedGoogle Scholar
  • 60 Fuchs TA, Brill A, Duerschmied D. , et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
    CrossrefPubMedGoogle Scholar
  • 61 von Brühl M-L, Stark K, Steinhart A. , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedGoogle Scholar
  • 62 Stark K, Philippi V, Stockhausen S. , et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 2016; 128 (20) 2435-2449
    CrossrefPubMedGoogle Scholar
  • 63 Semeraro F, Ammollo CT, Morrissey JH. , et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118 (07) 1952-1961
    CrossrefPubMedGoogle Scholar
  • 64 Brill A, Fuchs TA, Savchenko AS. , et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10 (01) 136-144
    CrossrefPubMedGoogle Scholar
  • 65 Borissoff JI, Joosen IA, Versteylen MO. , et al. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler Thromb Vasc Biol 2013; 33 (08) 2032-2040
    CrossrefPubMedGoogle Scholar
  • 66 Savchenko AS, Martinod K, Seidman MA. , et al. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost 2014; 12 (06) 860-870
    CrossrefPubMedGoogle Scholar
  • 67 de Boer OJ, Li X, Teeling P. , et al. Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction. Thromb Haemost 2013; 109 (02) 290-297
    Article in Thieme ConnectPubMedGoogle Scholar
  • 68 Lande R, Ganguly D, Facchinetti V. , et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 2011; 3 (73) 73ra19
    PubMedGoogle Scholar
  • 69 Soehnlein O, Ortega-Gómez A, Döring Y, Weber C. Neutrophil-macrophage interplay in atherosclerosis: protease-mediated cytokine processing versus NET release. Thromb Haemost 2015; 114 (04) 866-867
    Article in Thieme ConnectPubMedGoogle Scholar
  • 70 Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145 (03) 341-355
    CrossrefPubMedGoogle Scholar
  • 71 Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1262-1275
    CrossrefPubMedGoogle Scholar
  • 72 Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006; 47 (8, Suppl): C13-C18
    CrossrefPubMedGoogle Scholar
  • 73 Fujii K, Kobayashi Y, Mintz GS. , et al. Intravascular ultrasound assessment of ulcerated ruptured plaques: a comparison of culprit and nonculprit lesions of patients with acute coronary syndromes and lesions in patients without acute coronary syndromes. Circulation 2003; 108 (20) 2473-2478
    CrossrefPubMedGoogle Scholar
  • 74 Tian J, Ren X, Vergallo R. , et al. Distinct morphological features of ruptured culprit plaque for acute coronary events compared to those with silent rupture and thin-cap fibroatheroma: a combined optical coherence tomography and intravascular ultrasound study. J Am Coll Cardiol 2014; 63 (21) 2209-2216
    CrossrefPubMedGoogle Scholar
  • 75 Döring Y, Drechsler M, Soehnlein O, Weber C. Neutrophils in atherosclerosis: from mice to man. Arterioscler Thromb Vasc Biol 2015; 35 (02) 288-295
    CrossrefPubMedGoogle Scholar
  • 76 Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res 2012; 110 (06) 875-888
    CrossrefPubMedGoogle Scholar
  • 77 Simon DI, Zidar D. Neutrophils in atherosclerosis: alarmin evidence of a hit and run?. Circ Res 2012; 110 (08) 1036-1038
    CrossrefPubMedGoogle Scholar
  • 78 Pliyev BK, Menshikov M. Comparative evaluation of the role of the adhesion molecule CD177 in neutrophil interactions with platelets and endothelium. Eur J Haematol 2012; 89 (03) 236-244
    CrossrefPubMedGoogle Scholar
  • 79 Drechsler M, Döring Y, Megens RTA, Soehnlein O. Neutrophilic granulocytes - promiscuous accelerators of atherosclerosis. Thromb Haemost 2011; 106 (05) 839-848
    Article in Thieme ConnectPubMedGoogle Scholar
  • 80 Döring Y, Drechsler M, Wantha S. , et al. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res 2012; 110 (08) 1052-1056
    CrossrefPubMedGoogle Scholar
  • 81 Kougias P, Chai H, Lin PH, Yao Q, Lumsden AB, Chen C. Defensins and cathelicidins: neutrophil peptides with roles in inflammation, hyperlipidemia and atherosclerosis. J Cell Mol Med 2005; 9 (01) 3-10
    CrossrefPubMedGoogle Scholar
  • 82 Wang J, Sjöberg S, Tang T-T. , et al. Cathepsin G activity lowers plasma LDL and reduces atherosclerosis. Biochim Biophys Acta 2014; 1842 (11) 2174-2183
    PubMedGoogle Scholar
  • 83 Soehnlein O, Zernecke A, Eriksson EE. , et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 2008; 112 (04) 1461-1471
    CrossrefPubMedGoogle Scholar
  • 84 Wantha S, Alard J-E, Megens RTA. , et al. Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ Res 2013; 112 (05) 792-801
    CrossrefPubMedGoogle Scholar
  • 85 Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. Journal of Clinical Investigation [Internet]; 2008 . Available at: http://www.jci.org/articles/view/35535 . Accessed September 21, 2018
    PubMedGoogle Scholar
  • 86 Podrez EA, Schmitt D, Hoff HF, Hazen SL. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest 1999; 103 (11) 1547-1560
    CrossrefPubMedGoogle Scholar
  • 87 Podrez EA, Febbraio M, Sheibani N. , et al. Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J Clin Invest 2000; 105 (08) 1095-1108
    CrossrefPubMedGoogle Scholar
  • 88 Zhao B, Li Y, Buono C. , et al. Constitutive receptor-independent low density lipoprotein uptake and cholesterol accumulation by macrophages differentiated from human monocytes with macrophage-colony-stimulating factor (M-CSF). J Biol Chem 2006; 281 (23) 15757-15762
    CrossrefPubMedGoogle Scholar
  • 89 Paulson KE, Zhu S-N, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res 2010; 106 (02) 383-390
    CrossrefPubMedGoogle Scholar
  • 90 Wang Y, Wang GZ, Rabinovitch PS, Tabas I. Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages. Circ Res 2014; 114 (03) 421-433
    CrossrefPubMedGoogle Scholar
  • 91 Paulin N, Viola JR, Maas SL. , et al. Double-strand DNA sensing Aim2 inflammasome regulates atherosclerotic plaque vulnerability. Circulation 2018; 138 (03) 321-323
    CrossrefPubMedGoogle Scholar
  • 92 Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010; 207 (09) 1853-1862
    CrossrefPubMedGoogle Scholar
  • 93 Park B, Yim J-H, Lee H-K, Kim BO, Pyo S. Ramalin inhibits VCAM-1 expression and adhesion of monocyte to vascular smooth muscle cells through MAPK and PADI4-dependent NF-kB and AP-1 pathways. Biosci Biotechnol Biochem 2015; 79 (04) 539-552
    CrossrefPubMedGoogle Scholar
  • 94 Jang B, Kim HW, Kim J-S. , et al. Peptidylarginine deiminase inhibition impairs Toll-like receptor agonist-induced functional maturation of dendritic cells, resulting in the loss of T cell-proliferative capacity: a partial mechanism with therapeutic potential in inflammatory settings. J Leukoc Biol 2015; 97 (02) 351-362
    CrossrefPubMedGoogle Scholar
  • 95 Chang X, Yamada R, Suzuki A. , et al. Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 2005; 44 (01) 40-50
    CrossrefPubMedGoogle Scholar
  • 96 Chang H-H, Liu G-Y, Dwivedi N. , et al. A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22. JCI Insight 2016; 1 (17) e90045
    PubMedGoogle Scholar
  • 97 Lewis HD, Liddle J, Coote JE. , et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol 2015; 11 (03) 189-191
    CrossrefPubMedGoogle Scholar
  • 98 Dorweiler B, Torzewski M, Dahm M, Kirkpatrick CJ, Lackner KJ, Vahl CF. Subendothelial infiltration of neutrophil granulocytes and liberation of matrix-destabilizing enzymes in an experimental model of human neo-intima. Thromb Haemost 2008; 99 (02) 373-381
    Article in Thieme ConnectPubMedGoogle Scholar
  • 99 Gupta AK, Joshi MB, Philippova M. , et al. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett 2010; 584 (14) 3193-3197
    CrossrefPubMedGoogle Scholar
  • 100 Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis 2015; 74 (07) 1417-1424
    CrossrefPubMedGoogle Scholar
  • 101 Villanueva E, Yalavarthi S, Berthier CC. , et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 2011; 187 (01) 538-552
    CrossrefPubMedGoogle Scholar
  • 102 Rekhter MD. How to evaluate plaque vulnerability in animal models of atherosclerosis?. Cardiovasc Res 2002; 54 (01) 36-41
    CrossrefPubMedGoogle Scholar
  • 103 Jia H, Abtahian F, Aguirre AD. , et al. In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography. J Am Coll Cardiol 2013; 62 (19) 1748-1758
    CrossrefPubMedGoogle Scholar
  • 104 Franck G, Mawson T, Sausen G. , et al. Flow perturbation mediates neutrophil recruitment and potentiates endothelial injury via TLR2 in mice: implications for superficial erosion. Circ Res 2017; 121 (01) 31-42
    CrossrefPubMedGoogle Scholar
  • 105 Distelmaier K, Adlbrecht C, Jakowitsch J. , et al. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost 2009; 102 (03) 564-572
    Article in Thieme ConnectPubMedGoogle Scholar
  • 106 Ramaiola I, Padró T, Peña E. , et al. Changes in thrombus composition and profilin-1 release in acute myocardial infarction. Eur Heart J 2015; 36 (16) 965-975
    CrossrefPubMedGoogle Scholar
  • 107 Yunoki K, Naruko T, Sugioka K. , et al. Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion. Eur Heart J 2012; 33 (12) 1480-1490
    CrossrefPubMedGoogle Scholar
  • 108 Silvain J, Collet J-P, Nagaswami C. , et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 57 (12) 1359-1367
    CrossrefPubMedGoogle Scholar
  • 109 Rittersma SZH, van der Wal AC, Koch KT. , et al. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: a pathological thrombectomy study in primary percutaneous coronary intervention. Circulation 2005; 111 (09) 1160-1165
    CrossrefPubMedGoogle Scholar
  • 110 Riegger J, Byrne RA, Joner M. , et al; Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort (PRESTIGE) Investigators. Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium. Eur Heart J 2016; 37 (19) 1538-1549
    PubMedGoogle Scholar
  • 111 Darbousset R, Thomas GM, Mezouar S. , et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 2012; 120 (10) 2133-2143
    CrossrefPubMedGoogle Scholar
  • 112 Savchenko AS, Borissoff JI, Martinod K. , et al. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 2014; 123 (01) 141-148
    CrossrefPubMedGoogle Scholar
  • 113 Li X, de Boer OJ, Ploegmaker H. , et al. Granulocytes in coronary thrombus evolution after myocardial infarction—time-dependent changes in expression of matrix metalloproteinases. Cardiovasc Pathol 2016; 25 (01) 40-46
    CrossrefPubMedGoogle Scholar
  • 114 Liu DJ, Peloso GM, Yu H. , et al; Charge Diabetes Working Group; EPIC-InterAct Consortium; EPIC-CVD Consortium; GOLD Consortium; VA Million Veteran Program. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 2017; 49 (12) 1758-1766
    CrossrefPubMedGoogle Scholar
  • 115 Khera AV, Emdin CA, Drake I. , et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 2016; 375 (24) 2349-2358
    CrossrefPubMedGoogle Scholar
  • 116 Fernández-Friera L, Fuster V, López-Melgar B. , et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol 2017; 70 (24) 2979-2991
    CrossrefPubMedGoogle Scholar
  • 117 Kirii H, Niwa T, Yamada Y. , et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2003; 23 (04) 656-660
    CrossrefPubMedGoogle Scholar
  • 118 Duewell P, Kono H, Rayner KJ. , et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464 (7293): 1357-1361
    PubMedGoogle Scholar
  • 119 Mogayzel Jr PJ, Naureckas ET, Robinson KA. , et al; Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013; 187 (07) 680-689
    CrossrefPubMedGoogle Scholar
  • 120 Wang H, Wang C, Zhao M-H, Chen M. Neutrophil extracellular traps can activate alternative complement pathways. Clin Exp Immunol 2015; 181 (03) 518-527
    CrossrefPubMedGoogle Scholar
  • 121 Schreiber A, Rousselle A, Becker JU, von Mässenhausen A, Linkermann A, Kettritz R. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc Natl Acad Sci U S A 2017; 114 (45) E9618-E9625
    CrossrefPubMedGoogle Scholar
  • 122 Seok J, Warren HS, Cuenca AG. , et al; Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2013; 110 (09) 3507-3512
    CrossrefPubMedGoogle Scholar
  • 123 Horckmans M, Ring L, Duchene J. , et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J 2017; 38 (03) 187-197
    PubMedGoogle Scholar
  • 124 Soehnlein O, Wantha S, Simsekyilmaz S. , et al. Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Sci Transl Med 2011; 3 (103) 103ra98
    PubMedGoogle Scholar