591:
Skin Innate Lymphoid Cells Type 2 Activated by Keratinocyte-derived IL-25 promote IL-13-mediated skin allergic inflammation
Sunday, March 4, 2018: 2:45 PM
S330AB (Convention Center)
Juan-Manuel Leyva-Castillo,
RATIONALE: Lesional and non-lesional skin from patients with atopic dermatitis (AD) exhibit increased levels of IL-25 and its receptor (encoded by IL17RB). Whether IL-25 affects development of AD is not known.

METHODS: Wild type (WT) mice, Il17rb-/- mice, Il13-/- mice and mice which selectively lack IL-25R in ILC2s or IL-25 in keratinocytes were epicutaneously (EC) sensitized on tape stripped skin with ovalbumin (OVA) or saline. Cytokine mRNA expression was assessed by quantitative PCR, cell infiltrates were evaluated by flow cytometry, skin histology was examined by H&E staining, and splenocyte secretion of cytokines was measured by ELISA.

RESULTS: Using a mouse model of AD, in which allergic skin inflammation is elicited by application of OVA to tape stripped skin, we demonstrated that IL-25 signaling is important for the recruitment of CD4+ T cells, Il13 expression and IL-13-dependent epidermal hyperplasia in skin EC sensitized with OVA . However, IL-25 signaling was dispensable for the systemic response to OVA sensitization. Skin ILC2s, but not mast cells or CD4+ T cells, were the major source of IL-13 that was dependent on IL-25 signaling. Selective ablation of IL-25R in ILC2s or IL-25 in keratinocytes phenocopied the findings in Il17rb-/- mice.

CONCLUSIONS: These results demonstrate that keratinocyte-derived IL-25 activates skin ILC2s in epicutaneously sensitized skin to produce IL-13, and that this ILC2 derived IL-13 is important for epidermal hyperplasia and CD4+ T cell recruitment. Our results suggest that blocking the IL-25/IL-25R axis could be beneficial in patients with AD.