Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

Abstract

In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36, IL-36{beta} and IL-36{gamma} are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36{gamma}. This cytokine was strongly induced by IL-17A and efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors, by inducing a molecular signaling, such as phosphorylation of ERK1/2 and NF-{kappa}B P65 subunit. We highlighted the intense IL-17A- and IL-36{gamma}-dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. On HDMECs, IL-17A or IL-36{gamma} showed a synergic activity with TNF-, potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36{gamma} and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36{gamma} represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but not reduced inflammatory responses of HDMECs. On the other hand, inhibition of IL-36{gamma} released by IL-17A-treated keratinocytes impaired ICAM-1 expression in HDMECs. Taken together, our data demonstrated that IL-17A and IL-36{gamma} are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions.