Abstract
Abstract Psoriasis is a systemic autoimmune disease with a global prevalence of 2-3% and is strongly associated with metabolic dysfunction, vascular inflammation, and atherosclerotic cardiovascular disease (CVD). The IL-23/IL-17 pathway is critical for psoriatic inflammation. However, IL23/IL-17 blockade has no effect on CVD outcomes. Hence, the potential drivers of psoriatic CVD are still to be elucidated. IL-9-producing PU.1+/CD3+/CD4+ Th9 cells are found in the skin and circulation of patients with psoriasis. We found a significant association of Th9 cells with early radiographic atherosclerotic coronary artery disease in a psoriatic patient cohort. We observed an increase in aortic plaque size, and skin/aortic Th9 cells in a psoriatic atherogenesis model (IMQ-treated ApoE KO mice). To understand the involvement of IL-9 as a driver of the disease, we pharmacologically inhibited IL-9 in different modified disease models. IL-9 blockade-treated mice showed decreased skin inflammation compared to isotype-treated mice, accompanied by reduced aortic plaque formation. In vitro, IL-9 induced endothelial cell dysfunction through STAT3. Together, these results suggest that Th9/IL-9 may be a therapeutic target to prevent psoriasis-related atherosclerotic CVD. To further support our finding, we developed IL-9RKO/ApoE KO mice model, as well as conditional deletion of IL9R in various cell types. Further, transcriptomic profiling of endothelial cells will elucidate upon IL-9/STAT3 targets.
Published Version
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