Abstract
BackgroundPsoriasis patients exhibit an increased risk of atherothrombotic events, including myocardial infarction and stroke. Clinical evidence suggests that psoriasis patients with early onset and more severe disease have the highest risk for these co-morbidities, perhaps due to the extent of body surface involvement, subsequent levels of systemic inflammation, or chronicity of disease. We sought to determine whether acute or chronic skin-specific inflammation was sufficient to promote thrombosis.MethodsWe used two experimental mouse models of skin-specific inflammation generated in either an acute (topical Aldara application onto wild-type C57Bl/6 mice for 5 days) or chronic (a genetically engineered K5-IL-17C mouse model of psoriasiform skin inflammation) manner. Arterial thrombosis was induced using carotid artery photochemical injury (Rose Bengal-green light laser) and carotid artery diameters were measured post-clot formation. We also examined measures of clot formation including prothrombin (PT) and activated partial thromboplastin time (aPTT). Skin inflammation was examined histologically and we profiled plasma-derived lipids. The number of skin-draining lymph-node (SDLN) and splenic derived CD11b+Ly6Chigh pro-inflammatory monocytes and CD11b+Ly6G+ neutrophils was quantified using multi-color flow cytometry.ResultsMice treated with topical Aldara for 5 days had similar carotid artery thrombotic occlusion times to mice treated with vehicle cream (32.2 ± 3.0 vs. 31.4 ± 2.5 min, p = 0.97); in contrast, K5-IL-17C mice had accelerated occlusion times compared to littermate controls (15.7 ± 2.1 vs. 26.5 ± 3.5 min, p < 0.01) while carotid artery diameters were similar between all mice. Acanthosis, a surrogate measure of inflammation, was increased in both Aldara-treated and K5-IL-17C mice compared to their respective controls. Monocytosis, defined as elevated SDLN and/or splenic CD11b+Ly6Chigh cells, was significantly increased in both Aldara-treated (SDLN: 3.8-fold, p = 0.02; spleen: 2.0-fold, p < 0.01) and K5-IL-17C (SDLN: 3.4-fold, p = 0.02; spleen: 3.5-fold, p < 0.01) animals compared to controls while neutrophilia, defined as elevated SDLN and/or splenic CD11b+Ly6G+ cells, was significantly increased in only the chronic K5-IL-17C model (SDLN: 11.6-fold, p = 0.02; spleen: 11.3-fold, p < 0.01). Plasma-derived lipid levels, PT and aPTT times showed no difference between the Aldara-treated mice or the K5-IL-17C mice and their respective controls.ConclusionsChronic, but not acute, skin-specific inflammation was associated with faster arterial thrombotic occlusion. Increased numbers of splenic and SDLN monocytes were observed in both acute and chronic skin-specific inflammation, however, increased splenic and SDLN neutrophils were observed only in the chronic skin-specific inflammation model. Understanding the cellular response to skin-specific inflammation may provide insights into the cellular participants mediating the pathophysiology of major adverse cardiovascular events associated with psoriasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0738-z) contains supplementary material, which is available to authorized users.
Highlights
Psoriasis patients exhibit an increased risk of atherothrombotic events, including myocardial infarction and stroke
Aldara was applied to C57Bl/6 WT mice in an area that approximated the surface area of involved dorsal skin on the K5-IL-17C mice (Fig. 1a) and involved skin from both models developed similar increases in acanthosis, an often-used surrogate measure of inflammation for murine skin, compared to control cream-treated and littermate controls (Fig. 1b, bottom row compared to top row)
Acute, as well as chronic, skin-specific inflammation promotes the circulation and infiltration of proinflammatory CD11b+Ly6Chigh monocytes into the skin, significant changes in neutrophil percentages and occlusive distant vessel thrombosis occurs only in animals with chronic skin-specific inflammation
Summary
Psoriasis patients exhibit an increased risk of atherothrombotic events, including myocardial infarction and stroke. Clinical evidence suggests that psoriasis patients with early onset and more severe disease have the highest risk for these co-morbidities, perhaps due to the extent of body surface involvement, subsequent levels of systemic inflammation, or chronicity of disease. Individuals with psoriasis have an increased risk of developing and dying of cardiovascular disease (CVD) [7, 8]. Patients with severe psoriasis have an increased risk of experiencing an adverse cardiovascular event, such as stroke or myocardial infarction (MI) [9], and this occurs independent of other CVD risk factors including age, gender, smoking, diabetes, hypertension, and hyperlipidemia [8]. Causality between psoriasis and CVD is challenging to explore; many commonalities exist at the cellular and molecular levels between the two diseases [10, 11] and treating psoriasis patients with systemic anti-inflammatory drugs may improve associated CVD outcomes [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
