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Thromb Haemost 2017; 117(01): 176-187
DOI: 10.1160/TH16-06-0466
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

Coagulation factor XII induces pro-inflammatory cytokine responses in macrophages and promotes atherosclerosis in mice

Sandra Vorlova   #
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
,
Miriam Koch   #
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
,
Helga D. Manthey
2   Rudolf Virchow-Center for Experimental Medicine, University of Würzburg, Würzburg, Germany
,
Clement Cochain
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
,
Martin Busch
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
,
Sweena M. Chaudhari
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
,
David Stegner
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
2   Rudolf Virchow-Center for Experimental Medicine, University of Würzburg, Würzburg, Germany
,
Manuel Yepes
3   Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, and Department of Neurology, Veterans Affairs Medical Center, Atlanta, Georgia, USA
,
Kristina Lorenz
4   Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
5   Leibniz-Institut für Analytische Wissenschaften-ISAS-e. V., Dortmund, Germany
6   West German Heart and Vascular Center Essen, University Hospital Essen, Essen, Germany
,
Marc W. Nolte
7   CSL Behring GmbH, Marburg, Germany
,
Bernhard Nieswandt
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
2   Rudolf Virchow-Center for Experimental Medicine, University of Würzburg, Würzburg, Germany
,
Alma Zernecke
1   Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
› Author Affiliations Financial support: This work was supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB688, TP A22 to A. Z., TPA17 to K. L., TPA1 to B. N.), the Rudolf Virchow Center, Würzburg, Germany, and the Ministry for Innovation, Science and Research of the Federal State of North Rhine-Westphalia (to K. L.).
Further Information

Publication History

Received: 23 June 2016

Accepted after minor revision: 29 September 2016

Publication Date:
01 December 2017 (online)

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Summary

Atherosclerosis is considered a chronic inflammatory disease of the vessel wall. Coagulation pathways and immune responses contribute to disease development. The role of coagulation factor XII (FXII) in vascular inflammation, however, remains controversial. We here investigated the function of FXII in atherosclerosis using apolipoprotein E and FXII-deficient (F12−/−Apoe −/−) mice. Compared to F12 +/+ Apoe −/− controls, atherosclerotic lesion formation was reduced in F12−/−Apoe −/− mice. This was associated with a decrease in serum interleukin (IL)-1β and IL-12 levels and reduced expression of pro-inflammatory cytokines in the aorta in atherosclerotic F12−/−Apoe −/− mice, as well as diminished Th1-cell differentiation in the aorta, blood, and lymphoid organs. No changes in circulating bradykinin, thrombin-antithrombin-complexes or plasminogen were observed. Mechanistically, activated FXII (FXIIa) was revealed to directly induce bone marrow-derived macrophages to secrete pro-inflammatory cytokines, including tumour necrosis factor-α, IL-1β, IL-12, and IL-6. Exposure of bone marrow-derived antigen presenting cells to FXIIa similarly induced pro-inflammatory cytokines, and an enhanced capacity to trigger antigen-specific interferon γ-production in CD4+ T cells. Notably, bone-marrow derived macrophages were capable of directly activating FXII. Moreover, the induction of cytokine expression by FXIIa in macrophages occurred independently of FXII protease enzymatic activity and was decreased upon phospholipase C treatment, suggesting urokinase-type plasminogen activator receptor (uPAR) to confer FXIIa-induced cell signalling. These data reveal FXII to play an important role in atherosclerotic lesion formation by functioning as a strong inducer of pro-inflammatory cytokines in antigen-presenting cells. Targeting of FXII may thus be a promising approach for treating cardiovascular disease.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Atherosclerosis - inflammation - coagulation factor - cytokine - macrophage

# Equal contribution of these authors.


 

  • References

  • 1 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12: 204-212.
    CrossrefPubMedGoogle Scholar
  • 2 Borissoff JI, Spronk HM, ten Cate H. The haemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364: 1746-1760.
    CrossrefPubMedGoogle Scholar
  • 3 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422.
    CrossrefPubMedGoogle Scholar
  • 4 Seehaus S, Shahzad K, Kashif M. et al. Hypercoagulability inhibits monocyte transendothelial migration through protease-activated receptor-1-, phospholipase-Cbeta-, phosphoinositide 3-kinase-, and nitric oxide-dependent signalling in monocytes and promotes plaque stability. Circulation 2009; 120: 774-784.
    CrossrefPubMedGoogle Scholar
  • 5 Koch M, Zernecke A. The haemostatic system as a regulator of inflammation in atherosclerosis. IUBMB life 2014; 66: 735-744.
    CrossrefPubMedGoogle Scholar
  • 6 Maas C, Renne T. Regulatory mechanisms of the plasma contact system. Thromb Res 2012; 129 (Suppl. 02) S73-76.
    CrossrefPubMedGoogle Scholar
  • 7 Renne T, Pozgajova M, Gruner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-281.
    CrossrefPubMedGoogle Scholar
  • 8 Kuijpers MJ, van der Meijden PE, Feijge MA. et al. Factor XII regulates the pathological process of thrombus formation on ruptured plaques. Arterioscler Thomb Vasc Biol 2014; 34: 1674-1680.
    CrossrefPubMedGoogle Scholar
  • 9 Evangelho JS, Casali KR, Campos C. et al. Hypercholesterolemia magnitude increases sympathetic modulation and coagulation in LDLr knockout mice. Auton Neurosc 2011; 159: 98-103.
    PubMedGoogle Scholar
  • 10 Miller GJ, Esnouf MP, Burgess AI. et al. Risk of coronary heart disease and activation of factor XII in middle-aged men. Arterioscler Thomb Vasc Biol 1997; 17: 2103-2106.
    CrossrefPubMedGoogle Scholar
  • 11 Zito F, Drummond F, Bujac SR. et al. Epidemiological and genetic associations of activated factor XII concentration with factor VII activity, fibrinopeptide A concentration, and risk of coronary heart disease in men. Circulation 2000; 102: 2058-2062.
    CrossrefPubMedGoogle Scholar
  • 12 Colhoun HM, Zito F, Norman Chan N. et al. Activated factor XII levels and factor XII 46C>T genotype in relation to coronary artery calcification in patients with type 1 diabetes and healthy subjects. Atherosclerosis 2002; 163: 363-369.
    CrossrefPubMedGoogle Scholar
  • 13 Doggen CJ, Rosendaal FR, Meijers JC. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: Opposite and synergistic effects of factors XI and XII. Blood 2006; 108: 4045-4051.
    CrossrefPubMedGoogle Scholar
  • 14 Weber C, Meiler S, Doring Y. et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest 2011; 121: 2898-2910.
    CrossrefPubMedGoogle Scholar
  • 15 Cochain C, Koch M, Chaudhari SM. et al. CD8+ T Cells Regulate Monopoiesis and Circulating Ly6C–high Monocyte Levels in Atherosclerosis in Mice. Circulation Res 2015; 117: 244-253.
    CrossrefPubMedGoogle Scholar
  • 16 Newby AC. Do metalloproteinases destabilize vulnerable atherosclerotic plaques?. Curr Opin Lipidol 2006; 17: 556-561.
    CrossrefPubMedGoogle Scholar
  • 17 Lahoute C, Herbin O, Mallat Z. et al. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol 2011; 08: 348-358.
    CrossrefPubMedGoogle Scholar
  • 18 Ait-Oufella H, Sage AP, Mallat Z. et al. Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. Circ Res 2014; 114: 1640-1660.
    CrossrefPubMedGoogle Scholar
  • 19 Guilliams M, Ginhoux F, Jakubzick C. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 2014; 14: 571-578.
    CrossrefPubMedGoogle Scholar
  • 20 Zernecke A. Dendritic cells in atherosclerosis: evidence in mice and humans. Arterioscler Thromb Vasc Biol 2015; 35: 763-770.
    CrossrefPubMedGoogle Scholar
  • 21 Barbasz A, Kozik A. The assembly and activation of kinin-forming systems on the surface of human U-937 macrophage-like cells. Biol Chem 2009; 390: 269-275.
    PubMedGoogle Scholar
  • 22 Toossi Z, Sedor JR, Mettler MA. et al. Induction of expression of monocyte interleukin 1 by Hageman factor (factor XII). Proc Natl Acad Sci USA 1992; 89: 11969-11972.
    CrossrefPubMedGoogle Scholar
  • 23 Gobel K, Pankratz S, Asaridou CM. et al. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat Commun 2016; 07: 11626.
    CrossrefPubMedGoogle Scholar
  • 24 Helft J, Bottcher J, Chakravarty P. et al. GM-CSF Mouse Bone Marrow Cultures Comprise a Heterogeneous Population of CD11c(+)MHCII(+) Macrophages and Dendritic Cells. Immunity 2015; 42: 1197-1211.
    CrossrefPubMedGoogle Scholar
  • 25 Borissoff JI, Heeneman S, Kilinc E. et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 2010; 122: 821-830.
    CrossrefPubMedGoogle Scholar
  • 26 Hume DA. The Many Alternative Faces of Macrophage Activation. Front Immunol 2015; 06: 370.
    PubMedGoogle Scholar
  • 27 Chistiakov DA, Bobryshev YV, Orekhov AN. Changes in transcriptome of macrophages in atherosclerosis. J Cell Mol Med 2015; 19: 1163-1173.
    CrossrefPubMedGoogle Scholar
  • 28 Hagedorn I, Schmidbauer S, Pleines I. et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 2010; 121: 1510-1517.
    CrossrefPubMedGoogle Scholar
  • 29 LaRusch GA, Mahdi F, Shariat-Madar Z. et al. Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis. Blood 2010; 115: 5111-5120.
    CrossrefPubMedGoogle Scholar
  • 30 Tarui T, Andronicos N, Czekay RP. et al. Critical role of integrin alpha 5 beta 1 in urokinase (uPA)/urokinase receptor (uPAR, CD87) signalling. J Biol Chem 2003; 278: 29863-29872.
    CrossrefPubMedGoogle Scholar
  • 31 Chavakis T, Kanse SM, Yutzy B. et al. Vitronectin concentrates proteolytic activity on the cell surface and extracellular matrix by trapping soluble urokinase receptor-urokinase complexes. Blood 1998; 91: 2305-2312.
    PubMedGoogle Scholar
  • 32 Kleinschnitz C, Stoll G, Bendszus M. et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with haemostasis. J Exp Med 2006; 203: 513-518.
    CrossrefPubMedGoogle Scholar
  • 33 Stavrou E, Schmaier AH. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of haemostasis & thrombosis. Thromb Res 2010; 125: 210-215.
    CrossrefPubMedGoogle Scholar
  • 34 Simsekyilmaz S, Cabrera-Fuentes HA, Meiler S. et al. Role of extracellular RNA in atherosclerotic plaque formation in mice. Circulation 2014; 129: 598-606.
    CrossrefPubMedGoogle Scholar
  • 35 Klein S, Spannagl M, Engelmann B. Phosphatidylethanolamine participates in the stimulation of the contact system of coagulation by very-low-density lipoproteins. Arterioscler Thromb Vasc Biol 2001; 21: 1695-1700.
    PubMedGoogle Scholar
  • 36 Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008; 79: 360-376.
    CrossrefPubMedGoogle Scholar
  • 37 Zernecke A, Weber C. Chemokines in the vascular inflammatory response of atherosclerosis. Cardiovasc Res 2010; 86: 192-201.
    CrossrefPubMedGoogle Scholar
  • 38 Gutcher I, Becher B. APC-derived cytokines and T cell polarisation in autoimmune inflammation. J Clin Invest 2007; 117: 1119-1127.
    CrossrefPubMedGoogle Scholar
  • 39 Macatonia SE, Hosken NA, Litton M. et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 1995; 154: 5071-5079.
    PubMedGoogle Scholar
  • 40 Schreiber HA, Loschko J, Karssemeijer RA. et al. Intestinal monocytes and macrophages are required for T cell polarisation in response to Citrobacter rodentium. J Exp Med 2013; 210: 2025-2039.
    CrossrefPubMedGoogle Scholar
  • 41 Bettelli E, Carrier Y, Gao W. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235-238.
    CrossrefPubMedGoogle Scholar
  • 42 Gordon EM, Venkatesan N, Salazar R. et al. Factor XII-induced mitogenesis is mediated via a distinct signal transduction pathway that activates a mitogen-activated protein kinase. Proc Natl Acad Sci USA 1996; 93: 2174-2179.
    CrossrefPubMedGoogle Scholar
  • 43 Mahdi F, Madar ZS, Figueroa CD. et al. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood 2002; 99: 3585-3596.
    CrossrefPubMedGoogle Scholar
  • 44 Farris SD, Hu JH, Krishnan R. et al. Mechanisms of urokinase plasminogen activator (uPA)-mediated atherosclerosis: role of the uPA receptor and S100A8/A9 proteins. J Biol Chem 2011; 286: 22665-22677.
    CrossrefPubMedGoogle Scholar
  • 45 Larmann J, Jurk K, Janssen H. et al. Hepatic Overexpression of Soluble Urokinase Receptor (uPAR) Suppresses Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient (LDLR−/−) Mice. PloS one 2015; 10: e0131854.
    CrossrefPubMedGoogle Scholar
  • 46 Shnerb Ganor R, Harats D, Schiby G. et al. Factor XI Deficiency Protects Against Atherogenesis in Apolipoprotein E/Factor XI Double Knockout Mice. Arterioscler Thromb Vasc Biol 2016; 36: 475-481.
    CrossrefPubMedGoogle Scholar