Endothelial-Th9 interactions drive inflammatory cardiovascular disease development 3422

Abstract Description Psoriasis, a systemic autoimmune disease, is associated with metabolic dysfunction, vascular inflammation, and atherosclerotic cardiovascular disease (CVD). The IL-23/IL-17 pathway is critical for psoriatic inflammation; targeting these reduces skin, joint, and eye involvement but does not affect CVD outcomes. Hence, the drivers of psoriatic CVD are still to be elucidated. IL-9-producing Th9 cells are found in the circulation of psoriatic patients. We found a significant association of Th9 cells with early radiographic atherosclerotic CVD in a cohort of patients with psoriasis. We observed increased aortic plaque size, and skin/aortic Th9 cells in a psoriatic atherogenesis model (ApoE KO mice treated with IMQ). To understand the involvement of IL-9 in disease development, we inhibited IL-9 in this model. Mice treated with anti-IL-9 ab had decreased skin inflammation compared to isotype-treated mice, accompanied by reduced aortic plaque formation. A novel spontaneous psoriatic-atherogenesis model also corroborated this finding. In vitro, IL-9 induced endothelial cell (HAoEC) dysfunction through STAT3. Together, these results suggest that Th9/IL-9 may be a therapeutic target to prevent atherosclerotic CVD in psoriatic patients. Our findings were further supported by IL-9RKO/ApoEKO mice model, and conditional IL9R deletion model. Also, RNAseq data of IL9-treated HAoEC provided us with some leads about downstream targets of IL-9/STAT3 involved in psoriatic CVD development. Funding Sources Supported by NIAID intramural research program 1ZIAAI001251; National Psoriasis Foundation Topic Categories Cytokines and Chemokines and Their Receptors (CCR)