Dai Jun, Choo Min-Kyung, Park Jin Mo, Fisher David E
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, People's Republic of China; School of Pharmacy, University of Wisconsin-Madison, Wisconsin, USA.
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
J Invest Dermatol. 2017 Dec;137(12):2523-2531. doi: 10.1016/j.jid.2017.07.819. Epub 2017 Jul 31.
The retinoic acid receptor-related orphan receptors RORα and RORγ are critical for the functions of specific subsets of T cells and innate lymphoid cells, which are key drivers of inflammatory disease in barrier tissues. Here, we investigate the anti-inflammatory potential of SR1001, a synthetic RORα/γ inverse agonist, in mouse models of atopic dermatitis and acute irritant dermatitis. Topical treatment with SR1001 reduces epidermal and dermal features of MC903-induced atopic dermatitis-like disease and suppresses the production of type 2 cytokines and other inflammatory mediators in lesional skin. In the epidermis, SR1001 treatment blocks MC903-induced expression of TSLP and reverses impaired keratinocyte differentiation. SR1001 is also effective in alleviating acute dermatitis triggered by 12-O-tetradecanoylphorbol-13-acetate. Overall, our results suggest that RORα/γ are important therapeutic targets for cutaneous inflammation and suggest topical usage of inhibitory ligands as an approach to treating skin diseases of inflammatory etiology.
维甲酸受体相关孤儿受体RORα和RORγ对于特定亚群的T细胞和天然淋巴细胞的功能至关重要，而这些细胞是屏障组织中炎症性疾病的关键驱动因素。在此，我们研究了合成的RORα/γ反向激动剂SR1001在特应性皮炎和急性刺激性皮炎小鼠模型中的抗炎潜力。用SR1001进行局部治疗可减轻MC903诱导的特应性皮炎样疾病的表皮和真皮特征，并抑制病变皮肤中2型细胞因子和其他炎症介质的产生。在表皮中，SR1001治疗可阻断MC903诱导的TSLP表达，并逆转角质形成细胞分化受损。SR1001在减轻由12-O-十四烷酰佛波醇-13-乙酸酯引发的急性皮炎方面也有效。总体而言，我们的结果表明RORα/γ是皮肤炎症的重要治疗靶点，并提示局部使用抑制性配体作为治疗炎症性病因皮肤病的一种方法。
