Abstract 13186: Factor XII Deletion Induces Diverse Phenotypes in Preclinical Inflammation Models
Factor XII (FXII) is a member of the intrinsic coagulation pathway and is thought to play key roles in hemostasis, inflammation and immune responses. FXII is implicated in activation of the kallikrein-kinin system, liberation of pro-inflammatory bradykinin, complement activation, and interleukin-1 production. FXII may be involved in the pathogenesis of inflammatory conditions, and could play a role in the chronic low grade inflammation of atherosclerosis.
The role of FXII in mediating pro-inflammatory processes was evaluated using FXII knockout (KO) mice. Among the inflammation models evaluated were experimental autoimmune encephalitis (EAE) and dextran sodium sulfate-induced colitis (DSSC). FXII KO mice crossed with ApoE KO animals were used to assess atherosclerotic plaque development.
A marked protective effect of gene deletion was observed in complement-dependent EAE, a model used to study multiple sclerosis. The disease manifestation was significantly milder in FXII KO than wild type (WT) mice. The two major pathogenic cell populations in EAE were significantly decreased in spinal cords from FXII KO mice (macrophages: -59%; T cells: -24%; p<0.05) compared to WT mice. FXII KO mice also had significantly lower clinical severity scores than WT (i.e. Day 15: KO 1.1 ± 0.38; WT 3.3 ± 0.21; p<0.0001). By contrast, there was no apparent effect of FXII deletion in atherosclerosis, as aortic lesion area was similar in KO mice and WT mice on ApoE KO background. Finally, modest but significant exacerbation of disease was observed in FXII KO mice in DSSC, a model used to study epithelial inflammation in ulcerative colitis. More pronounced clinical colitis occurred in FXII KO than WT mice, as evidenced by significantly greater body weight loss over time (i.e. Day 8, WT: 85 ± 1.1%; KO: 80 ± 0.6% of baseline weight; p<0.01), and significantly shorter colon length (WT: 7.6 ± 0.14 cm; KO: 7.1 ± 0.13 cm; p<0.05) suggesting increased colonic inflammation.
The results indicate that deletion of the FXII gene modifies disease progression in EAE and DSSC, eliciting both therapeutically beneficial and disadvantageous phenotypes in these animal models. The data support a complex role for FXII as a contributor to pathways of inflammation.
- © 2013 by American Heart Association, Inc.