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 (F12Apoe) mice. Compared to F12Apoe controls, atherosclerotic lesion formation was reduced in F12Apoe 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 F12Apoe 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.

Bradykinin contributes to immune liver injury via B2R receptor-mediated pathways in trichloroethylene sensitized mice: A role in Kupffer cell activation

“…In our previous study, we found KKS activation and plasma BK expression increased significantly in TCE sensitized mice (Wang et al, 2016). Many studies have revealed BK stimulated macrophage activation and induced inflammatory cytokine expression in immune injury in other tissues (Feng et al, 2016;Vorlova et al, 2016;Desposito et al, 2015).…”

Phosphorylation-Dependent Differences in CXCR4-LASP1-AKT1 Interaction between Breast Cancer and Chronic Myeloid Leukemia

“…Cxcr4-floxed mice [32], kindly provided by Dr. Zou (Columbia University, New York, NY, USA, C57Bl/6 background), were crossed with C57Bl/6 CD11c-cre + mice to obtain CD11c-cre + Cxcr4 +/+ (WT) and CD11c-cre + Cxcr4 flox/flox mice (Cxcr4 −/− ) mice. BM-derived dendritic cells were generated from these, as described previously [33]. Briefly, femurs were removed from donor mice, the bone marrow was flushed and 1 × 10 6 cells were cultured in 24-well plates in RPMI-1640 with 2 mM L-Glutamine (Gibco BRL) containing 10% heat-inactivated fetal calf serum, 100 U/mL penicillin/streptomycin, and β-mercaptoethanol (50 µM, Gibco BRL) supplemented with 50 ng/mL GM-CSF (Peprotech).…”

Cell Receptor and Cofactor Interactions of the Contact Activation System and Factor XI

“…Purified DNA and RNA have been shown to bind and activate contact factors and enhance thrombin generation and clot formation in plasma based studies ( 21 , 22 ). Genetic knockout studies in murine models of cardiovascular disease and genetic linkage studies in humans have implicated the contact factors in contributing to diverse cardiovascular disease processes, including thrombosis ( 23 – 29 ), hypertension ( 30 ), atherosclerosis ( 31 , 32 ), and stroke ( 33 , 34 ).…”

“…The contact factors each have individual properties including recognizing foreign substances and interacting with different cell types ( 29 , 32 , 42 , 43 ) and bacteria ( 44 – 46 ). CAS has been implicated in viral pathogenesis ( 47 ) and as a component of the innate immune response ( 48 ).…”