IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice.
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.
Jin
Haoli
H
Division of Immunology, Children's Hospital and Harvard Medical SChool, Boston, MA 02115, USA.
Oyoshi
Michiko K
MK
Le
Yi
Y
Bianchi
Teresa
T
Koduru
Suresh
S
Mathias
Clinton B
CB
Kumar
Lalit
L
Le Bras
Séverine
S
Young
Deborah
D
Collins
Mary
M
Grusby
Michael J
MJ
Wenzel
Joerg
J
Bieber
Thomas
T
Boes
Marianne
M
Silberstein
Leslie E
LE
Oettgen
Hans C
HC
Geha
Raif S
RS
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
D007378:Interleukins; D054400:Receptors, CCR7; D053655:Receptors, Interleukin-21; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin; D020778:Matrix Metalloproteinase 2; D000098546:Interleukin-21