Peroxisome proliferator–activated receptor γ–mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice

Abstract

Dendritic cells (DCs) are one of the key regulators for the initiation of allergic responses in patients with atopic dermatitis (AD), being strongly triggered by epithelial cell-derived thymic stromal lymphopoietin (TSLP). Because peroxisome proliferator-activated receptor (PPAR) γ acts as a negative regulator in immune cells, suppressive properties of PPARγ in allergic responses have been proposed. Because pieces of evidence must be organized to identify the exact role of PPARγ in immune regulation, we explored the suppressive effects of a PPARγ agonist on various functions of DCs and the onset of AD in a murine model. Effects of rosiglitazone (RSG) on DCs that were derived from NC/Tnd mice, a model for human AD, were analyzed. RSG was administered to NC/Tnd mice to evaluate its preventive and therapeutic effects on the development of AD. RSG inhibited TSLP-induced DC maturation through downregulation of costimulatory molecules. TSLP-promoted expressions of chemokines in DCs were also suppressed by RSG treatment. Moreover, we showed the necessity of matrix metalloproteinase 9 in TSLP-promoted DC migration by using DCs derived from matrix metalloproteinase 9-deficient NC/Tnd mice, as well as the suppressive effect of PPARγ in the process. Daily oral administration of RSG to NC/Tnd mice before the onset of AD revealed a significant reduction in severity of skin lesions and scratching behavior. In mice treated with RSG, both expression of TSLP in the skin and maturation and migration of DCs were markedly suppressed. PPARγ can be provided as an inhibitory regulator of TSLP-stimulated DCs in the onset of allergic reactions.