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

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). IL-13 is expressed in atopic dermatitis skin lesions and plays an important role in pathogenesi...

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Published in:	Journal of allergy and clinical immunology 2020-06, Vol.145 (6), p.1606-1614.e4
Main Authors:	Leyva-Castillo, Juan Manuel, Galand, Claire, Mashiko, Shunya, Bissonnette, Robert, McGurk, Alex, Ziegler, Steven F., Dong, Chen, McKenzie, Andrew N.J., Sarfati, Marika, Geha, Raif S.
Format:	Article
Language:	eng
Subjects:	Allergens - immunology Animals Atopic dermatitis CD4-Positive T-Lymphocytes - immunology Cells, Cultured Dermatitis, Atopic - immunology Female Gene Expression - immunology Green Fluorescent Proteins - immunology Hypersensitivity - immunology IL-13 IL-25 ILC2 Inflammation - immunology Interleukin-13 - immunology Interleukins - immunology Keratinocytes - immunology Lymphocytes - immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Ovalbumin - immunology Skin - immunology Th2 Cells - immunology
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Summary:	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). IL-13 is expressed in atopic dermatitis skin lesions and plays an important role in pathogenesis of the disease. Our aim was to determine the role of IL-25 and ILC2s in a mouse model of antigen-driven allergic skin inflammation. 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. 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. 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 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. ILC2 activation by IL-25 is essential for IL-13 expression at sites of allergic skin inflammation. [Display omitted]
ISSN:	0091-6749 1097-6825