Abstract
Chronic inflammation is a critical component of atherogenesis, however, reliable human translational models aimed at characterizing these mechanisms are lacking. Psoriasis, a chronic inflammatory skin disease associated with increased susceptibility to atherosclerosis, provides a clinical human model that can be utilized to investigate the links between chronic inflammation and atherosclerosis development. We sought to investigate key biological processes in psoriasis skin and human vascular tissue to identify biological components that may promote atherosclerosis in chronic inflammatory conditions. Using a bioinformatics approach of human skin and vascular tissue, we determined IFN-γ and TNF-α are the dominant pro-inflammatory signals linking atherosclerosis and psoriasis. We then stimulated primary aortic endothelial cells and ex-vivo atherosclerotic tissue with IFN-γ and TNF-α and found they synergistically increased monocyte and T-cell chemoattractants, expression of adhesion molecules on the endothelial cell surface, and decreased endothelial barrier integrity in vitro, therefore increasing permeability. Our data provide strong evidence of synergism between IFN-γ and TNF- α in inflammatory atherogenesis and provide rationale for dual cytokine antagonism in future studies.
Highlights
Psoriasis is a common chronic inflammatory and hyper-proliferative skin disease that affects 2–3% of the US population and is associated with significant metabolic and cardiovascular co-morbidities[1,2,3]
76.9% of increased differentially expressed genes (DEGs) and 59.7% of decreased DEGs are observed in both tissues. (b) Further analysis utilizing Gene Ontology biological process categories demonstrated that 66 Gene Ontology biological processes are enriched in both psoriatic and advanced atherosclerotic plaque, and correspond to immunological processes such as inflammatory response, response to IFN-γ, regulation of T cell activation and antimicrobial responses
Of the 438 genes increased in psoriasis (FC > 2; FDR < 0.05), 76.9% were increased in advanced compared with early stage atherosclerotic plaques (P = 1.71 × 10−35) (Fig. 1a)
Summary
Psoriasis and atherosclerosis exhibit significant overlap of their transcriptomes. We hypothesized that there is significant overlap in the differentially expressed genes (DEGs) of lesional psoriasis skin and atherosclerotic plaques. While our data does not address whether skin derived IFN-γ is sufficient or necessary to trigger the development of atherosclerosis, data from animal models of psoriasis are strongly suggestive of this possibility[8] Our data supports this scenario, and demonstrates that exogenous IFN-γ along with TNF-α is a “lethal” combination, massively upregulating inflammatory responses in both vascular endothelium and established atherosclerotic lesions. Our study demonstrates significant overlap between the transcriptomes of atherosclerotic plaque and psoriatic skin, identifies key common cellular and cytokine responses involved in both diseases, provides insights into the mechanisms by which cutaneous inflammation may feed into and accelerate atherosclerosis, and demonstrates that therapeutic targeting of upregulated inflammatory pathways in patients with psoriasis leads to improvement and reduction in vascular diseases. Future studies should evaluate the potential use of dual antagonism of IFN-γ and TNF-α in reducing vascular diseases associated with psoriasis
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.
