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J Allergy Clin Immunol. 2020 Mar 13. pii: S0091-6749(20)30334-1. doi: 10.1016/j.jaci.2020.02.026. [Epub ahead of print]

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

Author information

1
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA. Electronic address: Manuel.LeyvaCastillo@childrens.harvard.edu.
2
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
3
Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
4
Innovaderm Research, Montreal, QC, Canada.
5
Immunology Program, Benaroya Research Institute, Seattle, WA, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
6
Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing, China.
7
Medical Research Council, Laboratory of Molecular Biology, Cambridge, Cambridgeshire, UK.
8
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA. Electronic address: raif.geha@childrens.harvard.edu.

Abstract

BACKGROUND:

Atopic dermatitis (AD) skin lesions demonstrate increased expression of interleukin 25 (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 AD skin lesions and plays an important role in the pathogenesis of the disease.

OBJECTIVE:

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 (eGFP) and mice that lack IL-25R, IL-25 in keratinocytes, 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 eGFP by flow cytometry. Gene expression was quantitated by RT-qPCR.

RESULTS:

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.

CONCLUSION:

ILC2 activation by IL-25 is essential for IL-13 expression at sites of allergic skin inflammation.

KEYWORDS:

Atopic dermatitis; IL-13; IL-25; ILC2s

PMID:
32179159
DOI:
10.1016/j.jaci.2020.02.026

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