Topical ROR Inverse Agonists Suppress Inflammation in Mouse Models of Atopic Dermatitis and Acute Irritant Dermatitis

The retinoic acid receptor-related orphan receptors ROR alpha and ROR gamma 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 ROR alpha/gamma 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 ROR alpha/gamma are important therapeutic targets for cutaneous inflammation and suggest topical usage of inhibitory ligands as an approach to treating skin diseases of inflammatory etiology.