Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark.
Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark; Department of Cardiology, Herlev-Gentofte University Hospital, Hellerup, Denmark.
Am J Pathol. 2018 Jun;188(6):1486-1496. doi: 10.1016/j.ajpath.2018.02.005. Epub 2018 Mar 12.
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.
银屑病是一种与多种合并症相关的慢性炎症性皮肤疾病，包括动脉粥样硬化。可能影响银屑病和动脉粥样硬化的疾病机制包括辅助性 T 细胞 1 和辅助性 T 细胞 17 细胞的激活。咪喹莫特应用是一种已建立的银屑病样皮肤炎症的小鼠模型。地高辛是一种心脏糖苷，它抑制辅助性 T 细胞 17 分化的主转录因子，维甲酸受体相关孤儿核受体γt，并减轻了小鼠中依赖于白介素-17 的病理。我们研究了周期性咪喹莫特诱导的银屑病样皮肤炎症是否会影响低密度脂蛋白受体缺陷型小鼠的动脉粥样硬化，以及地高辛是否会修饰这两种疾病。局部咪喹莫特应用增加了低密度脂蛋白受体缺陷型小鼠耳朵的厚度、角质形成细胞增殖和 CD3 T 细胞在皮肤中的积累。此外，咪喹莫特还影响了小鼠的全身系统，引起脾肿大以及白介素-17A 和血清淀粉样蛋白 A 的血浆水平升高。总的来说，咪喹莫特减少了主动脉弓正面的动脉粥样硬化，但没有影响主动脉根部的动脉粥样硬化。地高辛显著减少了咪喹莫特引起的耳朵增厚，对地高辛引起的全身炎症有不同的影响，并且没有影响动脉粥样硬化。总之，周期性咪喹莫特应用可长期诱导银屑病样皮肤病变，但可减轻低密度脂蛋白缺乏型小鼠的动脉粥样硬化。在该模型中，地高辛减少了皮肤炎症，但对动脉粥样硬化没有影响。
