title: A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis.
abstract: Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1(-/-) and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.
authors: Medical Research Council (MRC) Human Immunology Unit, National Institute for Health Research Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
authors: Maryam
authors: M
authors: Salimi
authors: Jillian L
authors: JL
authors: Barlow
authors: Sean P
authors: SP
authors: Saunders
authors: Luzheng
authors: L
authors: Xue
authors: Danuta
authors: D
authors: Gutowska-Owsiak
authors: Xinwen
authors: X
authors: Wang
authors: Li-Chieh
authors: LC
authors: Huang
authors: David
authors: D
authors: Johnson
authors: Seth T
authors: ST
authors: Scanlon
authors: Andrew N J
authors: AN
authors: McKenzie
authors: Padraic G
authors: PG
authors: Fallon
authors: Graham S
authors: GS
authors: Ogg
mesh_terms: D000485:Allergens / Q000737:chemistry; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism*; D000091344:Filaggrin Proteins; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012867:Skin / Q000378:metabolism
chemical_list: D000485:Allergens; D015820:Cadherins; D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C506536:IL33 protein, human; D018793:Interleukin-13; D020381:Interleukin-17; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D007381:Intermediate Filament Proteins