Murine atopic dermatitis responds to peroxisome proliferator-activated receptors α and β/δ (but not γ) and liver X receptor activators

Background: Atopic dermatitis (AD) is a chronic inflammatory dermatosis now increasingly linked to mutations that alter the structure and function of the stratum corneum. Activators of peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma and liver X receptor (LXR) regulate epidermal protein And lipid production, leading to superior barrier function. Additionally, some of these activators exhibit potent antihyperplastic and anti-inflammatory activity in irritant contact dermatitis and acute allergic contact dermatitis murine models. Objective: We evaluated the efficacy of PPAR/LXR activation in a hapten (oxazolone [Ox])-induced AD-like model (Ox-AD) in hairless mice. Methods: Ox-AD was established with 10 Ox challenges (every other day) on the flank. After the establishment of Ox-AD, twice-daily topical application with individual PPAR/LXR activators was then performed for 4 days, with continued Ox challenges every other day. The efficacy of topical PPAR/LXR activators to reduce parameters of Ox-AD was assessed physiologically, morphologically, and immunologically. Results: Certain topical activators of PPAR alpha, PPAR beta/delta, and LXR, but not activators of PPAR gamma, reversed the clinical dermatosis, significantly improved barrier function, and increased stratum corneum hydration in Ox-AD mice. In addition, the same activators, but again not PPAR gamma, largely reversed the immunologic abnormalities in Ox-AD mice, including the increased T(H)2 markers, such as tissue eosinophil/mast cell density, serum thymus and activation-related chemokine levels, the density of chemoattractant receptor-homologous molecule expressed on T(H)2-positive lymphocytes (but not serum IgE levels), and reduced IL-1 alpha and TNF-alpha activation, despite ongoing hapten challenges. Conclusion: These results suggest that topical applications of certain activators/ligands of PPAR alpha, PPAR beta/delta, and LXR could be useful for the treatment of AD in human subjects. (J Allergy Clin Immunol 2010;125:160-9.)