Exploring the Therapeutic Potential of Estrogen-Related Receptor γ Inverse Agonists in Atopic Dermatitis-like Lesions

초록

Estrogen-related receptor gamma (ERR gamma) has been reported to regulate various inflammation-related diseases. Herein, we attempted to evaluate the effects of DN200434 as a modulator for ERR gamma in mice with atopic dermatitis (AD). Levels of mRNA and protein expression for ERR gamma were evaluated in normal and DNCB-induced AD-diagnosed skin. The effects of DN200434 on the chemokines, inflammatory cytokines, and AKT/MAPK/NF kappa B pathway signaling were investigated in TNF-alpha/IFN-gamma-treated HaCaT cells. DNCB-induced AD mice received DN200434 intraperitoneally for 10 days. Epidermal thickness at the dorsal aspect of the inflamed skin, spleen index, serum IgE levels, and proinflammatory cytokine levels in the skin lesions were measured. Histopathological evaluations, including assessments of epidermal hyperplasia, dermal inflammation, hyperkeratosis, folliculitis, and mast cell counts, were performed to confirm diagnostic features. Significant elevations in ERR gamma expression at the RNA and protein levels were observed in DNCB-induced AD lesions. DN200434 suppressed chemokine and inflammatory cytokine expression and inhibited the elevated phosphorylation levels of AKT, ERK, p38, and NF kappa B in TNF-alpha/IFN-gamma-treated HaCaT cells. Treatment with DN200434 alleviated DNCB-induced AD symptoms. The histopathological score and levels of infiltrated mast cells were also markedly lower in DN200434-treated AD mice than in vehicle-treated AD mice. Consistently, DN200434 reduced the serum IgE level and mRNA expression of TNF alpha and IL-6 in AD-diagnosed lesions. Collectively, our findings indicated the feasibility of ERR gamma as a therapeutic target for the regulation of AD and that DN200434 can be a useful therapeutic agent in treating AD.

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