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.

Scavenging nucleic acid debris to combat autoimmunity and infectious disease

“…S3). Collectively, these skin damage studies indicate that local administration of NASs facilitates wound healing in a CLE-prone animal following injury by scavenging extracellular nucleic acids and reducing TLR7 and TLR9 activation (28,29), and this inhibition in turn limits sustained aberrant inflammation.…”

“…Skin lesion scoring was conducted in a blinded fashion by a trained veterinarian pathologist as previously described (28,29). Briefly, skin samples were collected, fixed in 10% (vol/vol) formalin, paraffin embedded (FFPE), and further processed for H&E staining.…”

IL-33 Promotes Food Anaphylaxis in Epicutaneously-Sensitized Mice By Targeting Mast Cells

“…Spleen single cell suspensions were cultured at 2×10 6 /ml in the presence of OVA (200 µg/ml) for 96 hours as described previously 34 . The levels of IL-4 and IL-13 were measured in supernatants by ELISA (eBioscience) following the manufacturer's instructions.…”

Mechanical Injury Polarizes Skin Dendritic Cells to Elicit a Th2 Response by Inducing Cutaneous TSLP Expression

“…We used the 6 hrs time point in order to capture DCs from injured skin prior to their migration to LN, and at a time when expression of inflammatory cytokines (IL-1, IL-6 and TNF-α) in tape stripped skin has peaked 7,8,18,19 . The percentages of CD11c + DCs in tape stripped and unmanipulated skin were comparable (Fig.…”