Abstract
Atopic dermatitis (AD) is a very common chronic inflammatory skin disease with defective immunologic barrier necessitating various topicals in addition to systemic treatments, but topical treatments are still unsatisfactory. A well-known facilitator of wound healing, epidermal growth factor (EGF) was also shown to inhibit inflammation and EGF receptor inhibitors increased Staphylococcus aureus (S. aureus). Thus, we investigated potential roles of EGF treatment in AD which is often aggravated by infection of S. aureus. We experimented how EGF work on expression of inflammatory cytokines and antimicrobial peptides (AMPs) in human epidermal keratinocyte (HEK) treated with heat-inactivated S. aureus (HKSA) in vitro and 2,4 dinitrochlorobenzene (DNCB) induced AD-like skin lesions in Nc/Nga mice. HKSA-induced IL-6 and NFκB expression and mRNA levels of p38 and EGF treatment reduced the level of these. Intriguingly, EGF increased the expression of human β defensin-2 (hBD-2) in HEK. In mice, both EGF and pimecrolimus groups showed less erythema with significantly decreased infiltrates of inflammatory cells and CD3+ T cells and decreased expression of thymic stromal lymphopoietin (TSLP) compared with untreated controls at 3 hr and 24 hr. TSLP expression was much more reduced in EGF group than in pimecrolimus group. In both EGF and pimecrolimus groups, murine β defensing-3 (mBD-3) was increased compared to the controls. EGF contributed to relieve inflammatory signals induced by S. aureus and AD-like skin lesions in Nc/Nga mice. Considering that AD is characterized by decreased AMPs with defective innate immune function leading to uncontrolled inflammation, EGF may be a potential topical treatment option in AD.
Highlights
Peripheral immunological tolerance is critical to prevent autoimmunity but detail of the mechanism has not been exactly understood
When peripheral Dsg3H1 T cells that developed in the absence of desmoglein 3 (Dsg3) as in Dsg3H1-Dsg3-/- mice were adoptively transferred to WT mice that express Dsg3, DsgH1 T cells disappeared in the periphery on Day 14
The elimination of Dsg3H1 T cells was affected in MHC II-/- (n 1⁄4 6), CCR7-/- mice (n 1⁄4 9) and WT recipients reconstituted by MHC II-/- bone marrow (BM) cells (n 1⁄4 12), but not affected in Aire-/, Langerin-DTA and DT-injected Langerin-DTR mice, indicating that the T cell elimination requires BM-derived antigen presenting cells (APCs) in a CCR7 dependent manner
Summary
Peripheral immunological tolerance is critical to prevent autoimmunity but detail of the mechanism has not been exactly understood. Significant decreases in acanthosis were observed (13Æ2 vs 41Æ4mm; P1⁄40.002) suggesting that IL-17C-IL-17RA signaling is critical for skin inflammation. We have previously shown a 15-fold increase in skin IL-17A and IL-17C (P
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