Affiliation:
1. Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute National Institute of Health Bethesda Maryland USA
2. Division of Dermatology and Venerology, Department of Medicine Karolinska Institutet Stockholm Sweden
Abstract
AbstractBackgroundBeta‐defensins (BDs) are antimicrobial peptides secreted upon epithelial injury. Both chemotactic and antimicrobial properties of BDs function as initial steps in host defence and prime the adaptive immune system in the body. Psoriasis, a chronic immune‐mediated inflammatory disease, has both visible cutaneous manifestations as well as known associations with higher incidence of cardiometabolic complications and vascular inflammation.ObjectivesWe aimed to investigate the circulating expression of beta‐defensin‐2 (BD2) in psoriasis at baseline compared to control subjects, along with changes in BD2 levels following biologic treatment at 1 year. The contribution of BD2 to subclinical atherosclerosis is also assessed. In addition, we have sought to unravel signalling mechanisms linking inflammation with BD2 expression.MethodsMultimodality imaging, as well as inflammatory biomarker assays, were performed in biological naïve psoriasis (n = 71) and non‐psoriasis (n = 53) subjects. A subset of psoriasis patients were followed for 1 year after biological intervention (antitumour necrosis factor‐α [TNF‐α], n = 30; anti‐interleukin17A [IL17A], n = 21). Measurements of circulating BD2 were completed by enzyme‐linked immunosorbent assay (ELISA). Using HaCaT‐transformed keratinocytes, expression of BD2 upon cytokine treatment was assessed by quantitative polymerase chain reaction and ELISA.ResultsHerein, we confirm that human circulating BD2 levels are associated with psoriasis, which attenuate upon biological interventions (anti‐TNF‐α, anti‐IL‐17A). A link between circulating BD2 and subclinical atherosclerosis markers was not observed. Furthermore, we demonstrate that IL‐17A‐driven BD2 expression occurs in a Phosphatidylinositol 3‐kinase (PI3‐kinase) and Rac1 GTPase‐dependent manner.ConclusionsOur findings expand on the potential role of BD2 as a tractable biomarker in psoriasis patients and describe the role of an IL‐17A‐PI3‐kinase/Rac signalling axis in regulating BD2 levels in keratinocytes.