title: Coagulation factor XII induces pro-inflammatory cytokine responses in macrophages and promotes atherosclerosis in mice.
abstract: 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.
authors: Sandra
authors: S
authors: Vorlova
authors: Miriam
authors: M
authors: Koch
authors: Helga D
authors: HD
authors: Manthey
authors: Clement
authors: C
authors: Cochain
authors: Martin
authors: M
authors: Busch
authors: Sweena M
authors: SM
authors: Chaudhari
authors: David
authors: D
authors: Stegner
authors: Manuel
authors: M
authors: Yepes
authors: Kristina
authors: K
authors: Lorenz
authors: Marc W
authors: MW
authors: Nolte
authors: Bernhard
authors: B
authors: Nieswandt
authors: Dr. Alma Zernecke, Universitätsklinikum Würzburg, Institut für Experimentelle Biomedizin, Josef-Schneider-Str. 2, 97080 Würzburg, Germany, Tel: +49 201 48331, Fax: +49 201 648341, E-mail: alma.zernecke@uni-wuerzburg.de.
authors: Alma
authors: A
authors: Zernecke
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism*; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005174:Factor XII / Q000235:genetics / Q000378:metabolism*; D005175:Factor XII Deficiency / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015956:Factor XIIa / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D055293:Receptors, Urokinase Plasminogen Activator; D005174:Factor XII; D015956:Factor XIIa
keywords: Atherosclerosis; coagulation factor; cytokine; inflammation; macrophage