Bae Ju Hyeon, Lee Sijoon, Lee Jae-Eon, Kim Sang Kyoon, Jeon Jae-Han, Jeon Yong Hyun
Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), 80 Cheombok-ro Dong-gu, Daegu 41061, Republic of Korea.
Department of Internal Medicine, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, 807 Hoguk-ro, Buk-gu, Daegu 41404, Republic of Korea.
Int J Mol Sci. 2025 Jul 20;26(14):6959. doi: 10.3390/ijms26146959.
Estrogen-related receptor γ (ERRγ) has been reported to regulate various inflammation-related diseases. Herein, we attempted to evaluate the effects of DN200434 as a modulator for ERRγ in mice with atopic dermatitis (AD). Levels of mRNA and protein expression for ERRγ were evaluated in normal and DNCB-induced AD-diagnosed skin. The effects of DN200434 on the chemokines, inflammatory cytokines, and AKT/MAPK/NFκB pathway signaling were investigated in TNF-α/IFN-γ-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 ERRγ 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 NFκB in TNF-α/IFN-γ-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 TNFα and IL-6 in AD-diagnosed lesions. Collectively, our findings indicated the feasibility of ERRγ as a therapeutic target for the regulation of AD and that DN200434 can be a useful therapeutic agent in treating AD.
据报道，雌激素相关受体γ（ERRγ）可调节多种炎症相关疾病。在此，我们试图评估DN200434作为特应性皮炎（AD）小鼠ERRγ调节剂的作用。在正常皮肤和二硝基氯苯（DNCB）诱导的AD诊断皮肤中评估ERRγ的mRNA和蛋白表达水平。在肿瘤坏死因子-α（TNF-α）/干扰素-γ（IFN-γ）处理的人永生化角质形成细胞（HaCaT细胞）中研究DN200434对趋化因子、炎性细胞因子以及AKT/丝裂原活化蛋白激酶（MAPK）/核因子κB（NFκB）信号通路的影响。给DNCB诱导的AD小鼠腹腔注射DN200434，持续10天。测量炎症皮肤背部的表皮厚度、脾脏指数、血清免疫球蛋白E（IgE）水平以及皮肤病变中的促炎细胞因子水平。进行组织病理学评估，包括评估表皮增生、真皮炎症、角化过度、毛囊炎和肥大细胞计数，以确认诊断特征。在DNCB诱导的AD病变中观察到ERRγ在RNA和蛋白水平显著升高。DN200434抑制趋化因子和炎性细胞因子表达，并抑制TNF-α/IFN-γ处理的HaCaT细胞中AKT、细胞外信号调节激酶（ERK）、p38和NFκB升高的磷酸化水平。DN200434治疗减轻了DNCB诱导的AD症状。在DN200434治疗的AD小鼠中，组织病理学评分和浸润肥大细胞水平也明显低于载体治疗的AD小鼠。一致地，DN200434降低了AD诊断病变中的血清IgE水平以及肿瘤坏死因子α（TNFα）和白细胞介素-6（IL-6）的mRNA表达。总体而言，我们的研究结果表明ERRγ作为调节AD的治疗靶点具有可行性，并且DN200434可以成为治疗AD的有用治疗药物。
