LAUSR

Career situation of first and presenting author Post-doctoral fellow. Introduction A large body of evidence indicates that IL-36R signaling plays an important role in the pathogenesis of psoriasis. For instance, IL-36 receptor (IL-36R)-deficient mice showed impaired development of imiquimod (IMQ)-induced psoriasis, but the cells in which IL-36R signaling is involved have not been identified. Objectives To assess the role of IL-36R signaling in keratinocytes in the development of IMQ-induced psoriasis. Methods We constructed an IL-36Rfl/fl mouse line in which exons 1 and 2 from the Il36r gene are flanked by loxP sites. Crossing these mice with K5-Cre transgenic mice induced a progeny with a specific deletion of Il36r in keratinocytes (IL-36RΔK). The selectivity of Il36r gene targeting in keratinocytes was confirmed by RT-qPCR and ex vivo cell stimulation by recombinant IL-36 using isolated keratinocytes and bone marrow differentiated dendritic cells. We then assessed the sensitivity of IL-36RΔK mice to IMQ-induced psoriasis, and compared it to mice presenting a complete IL-36R deficiency (IL-36R-/-) and to their respective littermate controls (IL-36+/+ and IL-36Rfl/fl). The severity of skin inflammation was assessed by ear thickness measured with a caliper. H and E staining was performed on treated and control ears. Total RNA was extracted from ears and mRNA levels of various cytokines were assessed by RT-qPCR. Results IL-36R-/- mice were strongly resistant to the induction of IMQ-induced psoriasis as assessed by ear thickness. IL-36RΔK mice showed a similar macroscopic protection as IL-36R-/- mice, demonstrating that IL-36 signaling in keratinocytes is critical in this model of psoriasis. Several pro-inflammatory genes upregulated by IMQ in IL-36R+/+ and IL-36Rfl/fl mice were not stimulated in neither IL-36R-/- nor in IL-36RΔK mice. These genes included notably IL-17A or IL-22, both known to be crucial in psoriasis. Histological findings in IMQ-induced psoriasis include keratinocyte altered differentiation and hyperproliferation as well as inflammatory cell infiltration. Surprisingly and in contrast to IL-36R-/-mice, epidermidis thickness was not reduced in IL-36RΔKcompared to IL-36Rfl/fl control mice. This finding suggests that IL-36 signaling in keratinocytes does not induce keratinocyte hyper-proliferation but rather controls the development of downstream inflammatory responses in IMQ-treated ears. Conclusions IL-36R signaling in keratinocytes is mandatory for the development of IMQ-induced psoriasis in mice. FACS studies are ongoing to characterize the inflammatory cell infiltrates in the different mouse lines. Disclosure of Interest None declared.