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


CONCLUSIONS
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.
Hatano
Yutaka
Y
Dermatology Service, Veterans Affairs Medical Center, University of California, San Francisco, CA, USA.
Man
Mao-Qiang
MQ
Uchida
Yoshikazu
Y
Crumrine
Debra
D
Mauro
Theodora M
TM
Feingold
Kenneth R
KR
Elias
Peter M
PM
Holleran
Walter M
WM
D000287:Administration, Topical; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D000071518:Liver X Receptors; D051379:Mice; D008812:Mice, Hairless; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010081:Oxazolone / Q000008:administration & dosage; D047493:PPAR alpha / Q000819:agonists*; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D018418:Th2 Cells / Q000276:immunology; D016896:Treatment Outcome
D016207:Cytokines; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047494:PPAR delta; D048068:PPAR-beta; D047492:Peroxisome Proliferator-Activated Receptors; D010081:Oxazolone