IL-21 R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice

被引:97
作者
Jin, Haoli [1 ]
Oyoshi, Michiko K. [1 ]
Le, Yi [2 ,3 ]
Bianchi, Teresa [4 ]
Koduru, Suresh [1 ]
Mathias, Clinton B. [1 ]
Kumar, Lalit [1 ]
Le Bras, Severine [1 ]
Young, Deborah [5 ]
Collins, Mary [5 ]
Grusby, Michael J. [6 ]
Wenzel, Joerg [7 ]
Bieber, Thomas [7 ]
Boes, Marianne [4 ]
Silberstein, Leslie E. [2 ,3 ]
Oettgen, Hans C. [1 ]
Geha, Raif S. [1 ]
机构
[1] Childrens Hosp, Div Immunol, Boston, MA 02115 USA
[2] Childrens Hosp, Joint Program Transfus Med, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Boston, MA USA
[4] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA
[5] Wyeth Res, Cambridge, MA USA
[6] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA
[7] Univ Bonn, Dept Dermatol & Allergy, D-5300 Bonn, Germany
基金
瑞士国家科学基金会;
关键词
STEADY-STATE CONDITIONS; IFN-GAMMA PRODUCTION; T-CELL-ACTIVATION; ATOPIC-DERMATITIS; DENDRITIC CELLS; IN-VIVO; LANGERHANS CELLS; MURINE MODEL; MAST-CELLS; TH1; CELLS;
D O I
10.1172/JCI32310
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 rl21r(-/-) 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 tracking 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.
引用
收藏
页码:47 / 60
页数:14
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