ILC2 activation by keratinocyte-derived IL-25 drives IL-13 production at sites of allergic skin inflammation

Juan Manuel Leyva-Castillo,Claire Galand,Shunya Mashiko,Robert Bissonnette,Alex Mcgurk,Steven F Ziegler,Chen Dong,Andrew N.J Mckenzie,Marika Sarfati,Raif S Geha

doi:10.1016/j.jaci.2020.02.026

Abstract

BackgroundAtopic dermatitis skin lesions demonstrate increased expression of IL-25 by keratinocytes and increased numbers of type 2 innate lymphoid cells (ILC2s) that express high levels of IL-25 receptor (IL-25R). IL-13 is expressed in atopic dermatitis skin lesions and plays an important role in pathogenesis of the disease.ObjectiveOur aim was to determine the role of IL-25 and ILC2s in a mouse model of antigen-driven allergic skin inflammation.MethodsWild-type mice; mice that express an Il13-driven enhanced green fluorescent protein; and mice that lack IL-25R, IL-25 in keratinocytes, or IL-13 or IL-25R in ILC2s were subjected to acute or chronic epicutaneous sensitization with ovalbumin. Sensitized skin was examined by histology for epidermal thickening. Cellular infiltrates were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was quantitated by RT quantitative PCR.ResultIn both acute and chronic antigen-driven allergic skin inflammation, signaling by keratinocyte-derived IL-25 in ILC2s is important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, and cutaneous expression of Il13 and the IL-13–dependent TH2-cell–attracting chemokines Cc17 and Ccl22. ILCs are the major source of IL-13 in acutely sensitized mouse skin, whereas T cells are its major source in chronically sensitized mouse skin.ConclusionILC2 activation by IL-25 is essential for IL-13 expression at sites of allergic skin inflammation.

Highlights

Atopic dermatitis skin lesions demonstrate increased expression of IL-25 by keratinocytes and increased numbers of type 2 innate lymphoid cells (ILC2s) that express high levels of IL-25 receptor (IL-25R)
To determine the role of IL-25 in acute allergic skin inflammation, we examined the response of Il17rb–/– mice to epicutaneous sensitization with ovalbumin over a 12-day period (Fig 1, A)
These findings demonstrate that IL-25 signaling is important for epidermal thickening and optimal accumulation of CD41 T cells at sites of acute allergic skin inflammation

Summary

Introduction

Atopic dermatitis skin lesions demonstrate increased expression of IL-25 by keratinocytes and increased numbers of type 2 innate lymphoid cells (ILC2s) that express high levels of IL-25 receptor (IL-25R). Objective: Our aim was to determine the role of IL-25 and ILC2s in a mouse model of antigen-driven allergic skin inflammation. Methods: Wild-type mice; mice that express an Il13-driven enhanced green fluorescent protein; and mice that lack IL-25R, IL-25 in keratinocytes, or IL-13 or IL-25R in ILC2s were subjected to acute or chronic epicutaneous sensitization with ovalbumin. Result: In both acute and chronic antigen-driven allergic skin inflammation, signaling by keratinocyte-derived IL-25 in ILC2s is important for epidermal hyperplasia, dermal infiltration by CD41 T cells, and cutaneous expression of Il13 and the IL-13–dependent TH2-cell–attracting chemokines Cc17 and Ccl[22]. Conclusion: ILC2 activation by IL-25 is essential for IL-13 expression at sites of allergic skin inflammation. (J Allergy Clin Immunol 2020;145:1606-14.)

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