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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.


 

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