Th9-arterial endothelial cell crosstalk promotes psoriatic atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death. Systemic autoimmune and inflammatory diseases are associated with increased ASCVD risk, severity, and mortality. The inflammatory cytokine interleukin 9 (IL-9) has been linked to murine atherogenesis, raising fundamental questions about the populations in which and the mechanisms by which IL-9 drives ASCVD.

Circulating T helper subsets and coronary computed tomography angiography data were analysed in patients with psoriasis. Murine models of psoriatic atherogenesis (imiquimod-ApoE^-/-, IL-23-ApoE^-/-, and Card14^ΔE138-ApoE^-/-) were investigated using IL-9 blockade or global and endothelial-specific Il9r deletion. Primary human aortic endothelial cells were used to assess IL-9/STAT3-dependent endothelial responses.

Here, we found that expansion of IL-9-producing T helper cells (Th9) was significantly associated with high-risk radiographic ASCVD in patients with the autoimmune disease psoriasis. Th9 cells were poised to migrate to coronary vessels and were identified in human atherosclerotic plaque from individuals with psoriasis. In vivo, murine inflammatory atherogenesis was prevented by IL-9 blockade and by IL-9 receptor (IL-9R) deletion in endothelial cells. In human arterial endothelial cells, IL-9R/STAT3 signalling promoted endothelial dysfunction via diverse mechanisms including adhesion, activation, angiogenesis, and release of leukocyte chemoattractants.

These findings suggest the Th9^high state may represent a novel psoriatic ASCVD endotype that could be targeted using precision approaches to prevent ASCVD in at-risk individuals.