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

Failla, C. M.; Capriotti, L.; Scarponi, C.; Mercurio, L.; Facchiano, F.; Morelli, M.; Rossi, S.; Pagnanelli, G.; Albanesi, C.; Cavani, A.; Madonna, S.

doi:10.1101/767400

bioRxiv · 10.1101/767400

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

Failla, C. M.·Capriotti, L.·Scarponi, C.·Mercurio, L.·Facchiano, F.·Morelli, M.·Rossi, S.·Pagnanelli, G.·Albanesi, C.·Cavani, A.·Madonna, S.

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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.

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Failla, C. M., Capriotti, L., Scarponi, C., Mercurio, L., Facchiano, F., Morelli, M., Rossi, S., Pagnanelli, G., Albanesi, C., Cavani, A., Madonna, S.. 2019-09-12. Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses. https://doi.org/10.1101/767400

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