title: IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice.
abstract: Atopic dermatitis (AD) is a common allergic inflammatory skin disease caused by a combination of intense pruritus, scratching, and epicutaneous (e.c.) sensitization with allergens. To explore the roles of IL-21 and IL-21 receptor (IL-21R) in AD, we examined skin lesions from patients with AD and used a mouse model of allergic skin inflammation. IL-21 and IL-21R expression was upregulated in acute skin lesions of AD patients and in mouse skin subjected to tape stripping, a surrogate for scratching. The importance of this finding was highlighted by the fact that both Il21r-/- mice and WT mice treated with soluble IL-21R-IgG2aFc fusion protein failed to develop skin inflammation after e.c. sensitization of tape-stripped skin. Adoptively transferred OVA-specific WT CD4+ T cells accumulated poorly in draining LNs (DLNs) of e.c. sensitized Il21r-/- mice. This was likely caused by both DC-intrinsic and nonintrinsic effects, because trafficking of skin DCs to DLNs was defective in Il21r-/- mice and, to a lesser extent, in WT mice reconstituted with Il21r-/- BM. More insight into this defect was provided by the observation that skin DCs from tape-stripped WT mice, but not Il21r-/- mice, upregulated CCR7 and migrated toward CCR7 ligands. Treatment of epidermal and dermal cells with IL-21 activated MMP2, which has been implicated in trafficking of skin DCs. These results suggest an important role for IL-21R in the mobilization of skin DCs to DLNs and the subsequent allergic response to e.c. introduced antigen.
authors.affiliation: Division of Immunology, Children's Hospital and Harvard Medical SChool, Boston, MA 02115, USA.
authors.forename: Haoli
authors.initials: H
authors.lastname: Jin
authors.forename: Michiko K
authors.initials: MK
authors.lastname: Oyoshi
authors.forename: Yi
authors.initials: Y
authors.lastname: Le
authors.forename: Teresa
authors.initials: T
authors.lastname: Bianchi
authors.forename: Suresh
authors.initials: S
authors.lastname: Koduru
authors.forename: Clinton B
authors.initials: CB
authors.lastname: Mathias
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.forename: Séverine
authors.initials: S
authors.lastname: Le Bras
authors.forename: Deborah
authors.initials: D
authors.lastname: Young
authors.forename: Mary
authors.initials: M
authors.lastname: Collins
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grusby
authors.forename: Joerg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Bieber
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
authors.forename: Hans C
authors.initials: HC
authors.lastname: Oettgen
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007114:Immunization; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D054400:Receptors, CCR7; D053655:Receptors, Interleukin-21; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin; D020778:Matrix Metalloproteinase 2; D000098546:Interleukin-21