J Allergy Clin Immunol. 2010 Jan;125(1):160-9.e1-5. doi: 10.1016/j.jaci.2009.06.049. Epub 2009 Oct 8.

Murine atopic dermatitis responds to peroxisome proliferator-activated receptors alpha and beta/delta (but not gamma) and liver X receptor activators.

Hatano Y, Man MQ, Uchida Y, Crumrine D, Mauro TM, Feingold KR, Elias PM, Holleran WM.

Source

Dermatology Service, Veterans Affairs Medical Center, University of California, San Francisco, CA, USA.

Abstract

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 PPARalpha, PPARbeta/delta, and LXR, but not activators of PPARgamma, 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 PPARgamma, 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-1alpha and TNF-alpha activation, despite ongoing hapten challenges.

CONCLUSION:

These results suggest that topical applications of certain activators/ligands of PPARalpha, PPARbeta/delta, and LXR could be useful for the treatment of AD in human subjects.