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. 2012 Aug;132(8):2067-75.
doi: 10.1038/jid.2012.112. Epub 2012 May 10.

Chronic skin-specific inflammation promotes vascular inflammation and thrombosis

Yunmei Wang  1 , Huiyun Gao, Candace M Loyd, Wen Fu, Doina Diaconu, Shijian Liu, Kevin D Cooper, Thomas S McCormick, Daniel I Simon, Nicole L Ward
Affiliations

Chronic skin-specific inflammation promotes vascular inflammation and thrombosis

Yunmei Wang et al. J Invest Dermatol. 2012 Aug.

Abstract

Patients with psoriasis have systemic and vascular inflammation and are at increased risk for myocardial infarction, stroke, and cardiovascular death. However, the underlying mechanism(s) mediating the link between psoriasis and vascular disease is incompletely defined. This study sought to determine whether chronic skin-specific inflammation has the capacity to promote vascular inflammation and thrombosis. Using the KC-Tie2 doxycycline-repressible (Dox-off) murine model of psoriasiform skin disease, spontaneous aortic root inflammation was observed in 33% of KC-Tie2 compared with 0% of control mice by 12 months of age (P=0.04) and was characterized by the accumulation of macrophages, T lymphocytes, and B lymphocytes, as well as by reduced collagen content and increased elastin breaks. Importantly, aortic inflammation was preceded by increases in serum tumor necrosis factor-α, IL-17A, vascular endothelial growth factor, IL-12, monocyte chemotactic protein-1, and S100A8/A9, as well as splenic and circulating CD11b(+)Ly-6C(hi) pro-inflammatory monocytes. Doxycycline treatment of old mice with severe skin disease eliminated skin inflammation and the presence of aortic root lesion in 1-year-old KC-Tie2 animals. Given the bidirectional link between inflammation and thrombosis, arterial thrombosis was assessed in KC-Tie2 and control mice; mean time to occlusive thrombus formation was shortened by 64% (P=0.002) in KC-Tie2 animals; and doxycycline treatment returned thrombosis clotting times to that of control mice (P=0.69). These findings demonstrate that sustained skin-specific inflammation promotes aortic root inflammation and thrombosis and suggest that aggressive treatment of skin inflammation may attenuate pro-inflammatory and pro-thrombotic pathways that produce cardiovascular disease in psoriasis patients.

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Figures

Figure 1
Figure 1
Aortic roots develop spontaneous vascular inflammation by 1 year of age in KC-Tie2 and not control animals. Aortic roots from control (a, c) and KC-Tie2 (b, d) animals stained with H&E. Quantitation of aortic root vessel wall area (e) demonstrates significant increases in area of KC-Tie2 mice (n=19) compared to control littermates (n=18). Immunohistological staining and quantitative analyses of positively stained CD45+ (f–h), Mac-3+ (i–k), CD3+ (l–n) and B220+ cells (o–q) (% positively stained area) within the aortic roots of representative control (f, l, i, o; n = 5) and KC-Tie2 mice with vascular inflammation (g, j, m, p; n=5) reveals significant increases in inflammatory cell infiltrates. * P <0.05 vs control animals. Scale bar = 100 μm.
Figure 2
Figure 2
Anatomical characterization of aortic arch lesions. Aortic roots from control (a, c, e, g) and KC-Tie2 (b, d, f, h) animals stained with Trichrome (a–d) or Verhoeff–van Gieson elastin (e–h) reveals decreased expression of collagen in Trichrome stained aortic arch tissue from KC-Tie2 mice and increases in the numbers of elastin breaks in Verhoeff–van Gieson elastin stained aortic root tissues. Scale bar = 100 μm.
Figure 3
Figure 3
Aortic root vascular inflammation develops in the presence of elevated systemic inflammation and monocytosis and independent of lower lipid levels. Proinflammatory cytokines are significantly elevated in KC-Tie2 mouse sera, including levels of MCP-1, IL-12p70, TNFα, IL-17A and VEGF (a; mean ± SEM; n=5–11 per group) and S100A8/A9 expression is increased in skin and serum of KC-Tie2 animals (b). KC-Tie2 animals have significantly less total cholesterol, triglycerides and HDL compared to control mice (c; mean ± SEM; n=8 per group; p values indicated for each lipid in table). 4-colour flow cytometry reveals significant increases in splenic proatherogenic monocytes (CD90loB220loCD49bloNK1.1loLy6GloCD11cloIAbloF4/80loCD11bhiLy-6Chi). Representative flow cytometry and quantification of CD11b+F4/80loLy-6Chi cells (d; mean ± SEM; n =4 spleens per group).* P <0.05 vs. control animals.
Figure 4
Figure 4
KC-Tie2 mice are pro-thrombotic. KC-Tie2 and control mice underwent experimental thrombosis; carotid artery blood flow was monitored continuously with a vascular flow probe, time to occlusion, defined as cessation of blood flow for 20 min, was recorded (a). Mean time (± SEM) to occlusive thrombus formation in control mice was 53 ± 8 minutes (n=10), and was shortened significantly in KC-Tie2 mice (19 ± 3 minutes; n=9; P=0.002). H&E stained carotid arteries from control and KC-Tie2 mice following Rose Bengal laser treatment. Note the fibrin-platelet rich thrombi with some red blood cells in the lumen of carotid arteries of KC-Tie2 and not control mice (b). *P<0.05 vs control animals. Scale bar = 100 μm.
Figure 5
Figure 5
Repressing skin inflammation improves aortic root lesions and thrombosis clotting times. Seven month old KC-Tie2 mice (n=9) and control littermates (n=9) were treated with doxycycline to repress transgene expression and reverse skin inflammation. Aortic roots from representative 1 year old control (a, c, e) and KC-Tie2 (b, d, f) animals stained with H&E (a–b), Trichrome (c–d) and elastin (e–f). No aortic root lesions were observed in any control or KC-Tie2 doxycycline treated mice. (g) KC-Tie2 and control mice treated with doxycycline for 6 weeks underwent experimental thrombosis; mean time (± SEM) to occlusive thrombus formation was not significantly different between control mice treated with doxycycline (31 ± 8 minutes; n=10) and KC-Tie2 mice treated with doxycycline (36 ± 9 minutes; n=10; P=0.69). Scale bar = 100 μm.
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