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

Sandra Vorlova; Miriam Koch; Helga D. Manthey; Clement Cochain; Martin Busch; Sweena M. Chaudhari; David Stegner; Manuel Yepes; Kristina Lorenz; Marc W. Nolte; Bernhard Nieswandt; Alma Zernecke

doi:10.1160/TH16-06-0466

Thrombosis and Haemostasis, Inhaltsverzeichnis

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^#

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

,

Miriam Koch^#

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

,

Helga D. Manthey

²Rudolf Virchow-Center for Experimental Medicine, University of Würzburg, Würzburg, Germany

,

Clement Cochain

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

,

Martin Busch

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

,

Sweena M. Chaudhari

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

,

David Stegner

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

²Rudolf Virchow-Center for Experimental Medicine, University of Würzburg, Würzburg, Germany

,

Manuel Yepes

³Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, and Department of Neurology, Veterans Affairs Medical Center, Atlanta, Georgia, USA

,

Kristina Lorenz

⁴Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany

⁵Leibniz-Institut für Analytische Wissenschaften-ISAS-e. V., Dortmund, Germany

⁶West German Heart and Vascular Center Essen, University Hospital Essen, Essen, Germany

,

Marc W. Nolte

⁷CSL Behring GmbH, Marburg, Germany

,

Bernhard Nieswandt

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

²Rudolf Virchow-Center for Experimental Medicine, University of Würzburg, Würzburg, Germany

,

Alma Zernecke

¹Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

› Institutsangaben

Abstract

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

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Referenzen

References
1 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12: 204-212.
2 Borissoff JI, Spronk HM, ten Cate H. The haemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364: 1746-1760.
3 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422.
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.
5 Koch M, Zernecke A. The haemostatic system as a regulator of inflammation in atherosclerosis. IUBMB life 2014; 66: 735-744.
6 Maas C, Renne T. Regulatory mechanisms of the plasma contact system. Thromb Res 2012; 129 (Suppl. 02) S73-76.
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.
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.
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.
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.
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.
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.
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.
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.
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.
16 Newby AC. Do metalloproteinases destabilize vulnerable atherosclerotic plaques?. Curr Opin Lipidol 2006; 17: 556-561.
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.
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.
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.
20 Zernecke A. Dendritic cells in atherosclerosis: evidence in mice and humans. Arterioscler Thromb Vasc Biol 2015; 35: 763-770.
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.
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.
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.
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.
25 Borissoff JI, Heeneman S, Kilinc E. et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 2010; 122: 821-830.
26 Hume DA. The Many Alternative Faces of Macrophage Activation. Front Immunol 2015; 06: 370.
27 Chistiakov DA, Bobryshev YV, Orekhov AN. Changes in transcriptome of macrophages in atherosclerosis. J Cell Mol Med 2015; 19: 1163-1173.
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.
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.
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.
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.
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.
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.
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.
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.
36 Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008; 79: 360-376.
37 Zernecke A, Weber C. Chemokines in the vascular inflammatory response of atherosclerosis. Cardiovasc Res 2010; 86: 192-201.
38 Gutcher I, Becher B. APC-derived cytokines and T cell polarisation in autoimmune inflammation. J Clin Invest 2007; 117: 1119-1127.
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.
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.
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.
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.
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.
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.
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.
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.

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