898 The role of keratinocyte cytokines in the IL-17A-induced asymmetric stem cell self-renewal in psoriasis

We previously showed that the hyperproliferation of psoriasis is associated with increased asymmetric stem cell (SC) self-renewal divisions and that IL17A increases asymmetric SC self-renewal divisions in keratinocytes. This study focused on 1) whether IL17A inhibition (secukinumab) would prevent the alteration in SC behavior associated with psoriasis, and 2) the effect of downstream cytokines produced by keratinocytes after IL17A treatment. To study SC self-renewal, psoriasis keratinocytes were treated with secukinumab or vehicle and foreskin keratinocytes were treated with IL17A, IL17A+secukinumab, or vehicle. We then examined the role of downstream cytokines produced by keratinocytes after IL17A treatment using a Multianalyte ELISArray Kit and analyzed of asymmetric SC self-renewal divisions. The proportion of asymmetric SC self-renewal divisions was decreased in psoriasis treated with secukinumab (34.7±11%) to levels approaching normal skin (25.7±6.4%, P=0.29). IL17A treatment of foreskin keratinocytes increased the proportion of asymmetric divisions (55.8% vs. vehicle 33.3%). Secukinumab (200 μg/mL) prevented the IL17A-induced increase in asymmetric SC self-renewal divisions (38.2% vs. untreated 55.8%). IL17A treatment of keratinocytes increased IL6, GM-CSF, and IL8 production (P≤0.05) but not TNFa, IL1b, IL12, IL4, IL10, IL12, or IFNg. Treatment of keratinocytes with IL6 (51.2±1.0%) or GM-CSF (47.8±2.7%), significantly increased asymmetric SC self-renewal divisions vs. vehicle (37.3±0.8%, 34.2±1.0%, respectively) (P<0.05). Treatment of keratinocytes with TNF-a or IL8 did not change asymmetric SC self-renewal divisions significantly. Thus, secukinumab, an IL17A inhibitor, reverses the increased asymmetric SC self-renewal divisions in psoriasis. Also, multiple downstream cytokines induced by IL17A treatment increase asymmetric SC self-renewal divisions in normal keratinocytes.