title: Chronic, not acute, skin-specific inflammation promotes thrombosis in psoriasis murine models.
abstract: BACKGROUND
  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. We sought to determine whether acute or chronic skin-specific inflammation was sufficient to promote thrombosis.
  
  
  METHODS
  We 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(+)Ly6C(high) pro-inflammatory monocytes and CD11b(+)Ly6G(+) neutrophils was quantified using multi-color flow cytometry.
  
  
  RESULTS
  Mice 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(+)Ly6C(high) 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.
  
  
  CONCLUSIONS
  Chronic, 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.
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. jxg406@case.edu.|Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. jxg406@case.edu.
authors.forename: Jackelyn B
authors.initials: JB
authors.lastname: Golden
authors.affiliation: Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. yxw93@case.edu.
authors.forename: Yunmei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. yxf107@case.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fritz
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. dxd76@case.edu.
authors.forename: Doina
authors.initials: D
authors.lastname: Diaconu
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. xxz275@case.edu.|Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. xxz275@case.edu.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA. smd3@case.edu.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Debanne
authors.affiliation: Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. daniel.simon@uhhospitals.org.|The Murdough Family Center for Psoriasis, Case Western Reserve University, Cleveland, OH, USA. daniel.simon@uhhospitals.org.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Simon
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. tsm4@case.edu.|The Murdough Family Center for Psoriasis, Case Western Reserve University, Cleveland, OH, USA. tsm4@case.edu.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. nlw4@cwru.edu.|The Murdough Family Center for Psoriasis, Case Western Reserve University, Cleveland, OH, USA. nlw4@cwru.edu.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D007249:Inflammation / Q000150:complications / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011565:Psoriasis / Q000150:complications*; D013927:Thrombosis / Q000150:complications*