Epicutaneous Application of Imiquimod to Model Psoriasis-Like Skin Disease Induces Water-Saving Aestivation Motifs and Vascular Inflammation

摘要

TO THE EDITOR:The chronic inflammatory skin disease psoriasis is associated with cardiovascular disease leading to a reduced life expectancy (Mehta et al., 2010). This makes strategies to improve cardiovascular risk management in patients with psoriasis essential (Garshick and Berger, 2022), for which a better understanding of the skin-vasculature crosstalk lays the foundation.Independently of the classical cardiovascular risk factors, the inflammatory state itself drives cardiovascular comorbidity in these patients (Mehta et al., 2010). We have previously shown that mice overexpressing IL-17A—one of the central cytokines in psoriasis—in kerati-nocytes (K14-IL-17Aind/+ mice) (Croxford et al., 2014) suffer from vascular dysfunction and hypertension, besides a severe psoriasis-like skin phenotype (Karbach et al., 2014). Vascular dysfunction depended on IL-17A-driven invasion of myeloid cells, capable to produce vast amounts of reactive oxygen and nitrogen species, into the aortic vessel wall (Karbach et al., 2014). However, this is only one puzzle piece of the multifaceted mechanistic background of the cardiovascular manifestation of psoriasis. We have just recently shown that the skin is a powerful contributor to systemic blood pressure homeostasis using chronic severe psoriasis as a model for skin water loss (Wild et al., 2021) and that skin inflammation in psoriasis correlates with dermal sodium accumulation (Maifeld et al., 2022). The inflammatory disruption of the skin barrier resulted in severe transcutaneous water loss in K14-IL-17Aind/+ mice with chronic severe psoriasis (Wild et al., 2021). To avoid lethal dehydration, mice utilized aestivation-like water conservation motifs (Wild et al, 2021), which can also stabilize body water in other states of chronic water loss (Kitada et al, 2017; Kovarik et al., 2021). On the one hand, these motifs consisted of catabolic muscle wasting to provide nitrogen for increased urea osmolyte levels in the skin and kidney to avoid further water loss (Wild et al., 2021). On the other hand, they affected vascular tone, resulting in arterial hypertension (Wild et al, 2021). To date, it is still unclear when the first vascular effects occur in psoriasis. This aspect is of paramount clinical relevance because it ultimately turns the patient with psoriasis into a patient of high cardiovascular risk. To address this question, we analyzed whether even a short phase of skin inflammation is sufficient to cause severe skin water loss and subsequent water conservation. Furthermore, we aimed to elucidate the time point when epicuta-neous imiquimod (IMQ) treatment begins to evoke vascular inflammation.