Background

Psoriasis, the most common chronic skin disease worldwide, is classified as an independent cardiovascular risk factor. In the pathophysiology, the IL-23/IL-17A axis forms the crucial pathway. A variety of genetic and inducible acute experimental models exist reproducing aspects of the human disease in mice. In mice overexpressing IL-17A in keratinocytes or dendritic cells, we previously could reproduce both disease aspects - cutaneous hallmarks and the vascular phenotype. For the most commonly used Imiquimod (IMQ)-induced psoriasis-like skin disease model, cardiovascular aspects haven’t been studied yet. In this model, topical application of Imiquimod, a Toll-like receptor 7/8 agonist, results in an inflammatory response resembling features of human psoriasis. Therefore, we examined vascular and hemodynamic effects of this most popular murine psoriasis model.

Methods

C57BL/6J mice were treated with 5% IMQ or sham cream on their back skin. During treatment, we daily measured bodyweight, skin thickness, skin water loss with a Tewameter and erythema. After 10 days, aortic relaxation studies were performed. For assessment of vascular inflammation, inflammatory cell infiltration into the aortic tissue was investigated by flow cytometric analysis. To record physical activity, blood pressure and heart rate, carotid catheters were implanted two weeks before treatment with IMQ. Blood pressure and heart rate were continuously recorded by receiver platforms.

Results

IMQ treatment resulted in severe local skin inflammation, with a peak of erythema and scaling at d6. IMQ induced a skin barrier defect resulting in a 7-fold increase of transcutaneous water loss (from 11±6 ml/m²h to 77±30 ml/m²h). Physical activity dropped more than 50% after d1 of treatment before normalizing at d7. Telemetric recording revealed a reflex tachycardia at 1d of IMQ-application (from 492±21 bpm to 524 ±20 bpm) followed by a significant reduction of heart rate for the next two days (456±18bpm). Arterial blood pressure showed a similar trend: after a fast increase (from 120±13 mmHg to 127±18 mmHg), systolic pressure dropped below baseline at d2/3 with a subsequent recovery. We could display a highly significant positive correlation between blood pressure and heart rate during the treatment (R=0.6; p ≤ 0.0001). Aortas from animals after 10d of IMQ-treatment showed an increased infiltration of CD45⁺ and CD11b⁺ inflammatory cells but no change of responsiveness to endothelium dependent (ACh) and independent (GTN) vasodilators in organ chamber studies.  

Conclusion

Skin treatment with IMQ had severe implications on hemodynamic parameters: After an initial peak of heart rate and blood pressure, mice showed significantly lower values for two days with a subsequent recovery. Moreover, bodyweight and physical activity were significantly altered during treatment. Our data indicate that in addition to skin inflammation, inflammatory skin barrier disruption by IMQ with subsequent massive skin water loss forces a compensatory whole-body response. Furthermore, 10 days of skin treatment with IMQ resulted in vascular inflammation reflected by infiltration of inflammatory cells in the aortic wall without mediating vascular dysfunction. In summary, we could reveal that IMQ-induced psoriasis, as the most popular murine psoriasis model worldwide, not only affects the skin, but also has extensive effects on the whole circulatory system.