Abstract
Psoriasis is a chronic inflammatory skin disorder associated with several comorbidities, including atherosclerosis. Disease mechanisms that may affect both psoriasis and atherosclerosis include activation of T helper 1 and T helper 17 cells. Imiquimod application is an established mouse model of psoriasis-like skin inflammation. The cardiac glycoside digoxin inhibits the master transcription factor of T helper 17 differentiation, retinoid acid receptor-related orphan nuclear receptor γt, and attenuates IL-17-dependent pathologies in mice. We investigated whether cyclic imiquimod-induced psoriasis-like skin inflammation affects atherosclerosis in low-density lipoprotein receptor-deficient mice and whether digoxin modifies either disease. Topical imiquimod application increased ear thickness, keratinocyte proliferation, and accumulation of CD3+ T cells in the skin of low-density lipoprotein receptor-deficient mice. Also, imiquimod affected the mice systemically with induction of splenomegaly as well as increased plasma levels of IL-17A and serum amyloid A. Overall, imiquimod reduced atherosclerosis in the aortic arch en face, but it did not affect atherosclerosis in the aortic root. Digoxin significantly reduced the imiquimod-induced ear thickening, had divergent effects on imiquimod-induced systemic inflammation, and did not affect atherosclerosis. In conclusion, cyclic imiquimod applications can be used for long-term induction of psoriasis-like skin lesions, but they attenuate atherosclerosis in low-density lipoprotein-deficient mice. In this model, digoxin reduces skin inflammation, but it has no effect on atherosclerosis.