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, 125 (1), 160-9.e1-5

Murine Atopic Dermatitis Responds to Peroxisome Proliferator-Activated Receptors Alpha and Beta/Delta (But Not Gamma) and Liver X Receptor Activators

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Murine Atopic Dermatitis Responds to Peroxisome Proliferator-Activated Receptors Alpha and Beta/Delta (But Not Gamma) and Liver X Receptor Activators

Yutaka Hatano et al. J Allergy Clin Immunol.

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.

Figures

Figure 1
Figure 1. A: PPARα, β/δ, and LXR Activators Reverse Murine Ox-AD
Gross appearance after applications of ligands for LXR(10mM T0901317), PPARα(10mM WY14643), β/δ(4mM GW1514), and γ (10mM ciglitazone), and glucocorticoid (GC; 0.05% clobetasol). As a vehicle control (Ox+vehicle), propylene glycol and ethanol (7:3) alone was applied. B: Histological appearance after treatment with ligands for LXR, PPARα, β/δ and γ, and the glucocorticoid (GC), clobetasol. (H&E staining) C: Quantitative changes in epidermal hyperplasia, in LXR, PPARα, β/δ, and γ ligands, and the glucocorticoid (GC), clobetasol - treated mice were assessed in coded, randomized micrographs (see Methods). D: PCNA-positive cells counts (per 50 μm) were quantitated as described in Methods. ETOH: Normal skin in which ethanol was applied instead of Ox (n=30 measurements each from 3 separate samples for epidermal hyperplasia assessment; and 22-27 measurements each for PCNA assessment).
Figure 2
Figure 2. Ligands of LXR, PPARα, β/δ, and Clobetasol Normalize Epidermal Function
Epidermal barrier function, assessed as transepidermal water loss (TEWL), surface pH, and SC hydration were measured and topical applications of the LXR, PPARα, β/δ and PPARγ ligands, as well as the glucocorticoid (GC), clobetasol propionate, and the vehicle (Veh) were performed as described in Methods. ETOH = control group normal mice. Each experiment was repeated twice and representative data are displayed. For TEWL and SC hydration, n=24 measurements from 5 different animals in each group; for pH n=16 measurements from the same animals. * p<0.05 (day 1 vs. either day 3 or day 5).
Figure 3
Figure 3. Topical LXR Ligand Normalizes Lamellar Body Secretion and Lamellar Bilayer Structure in Ox-AD Mice
Stratum corneum of oxalozone (Ox) + vehicle (Veh)-treated skin sites demonstrate incomplete formation of lamellar bilayers (Panel A, open arrows and asterisks), while Ox + LXR ligand (TO; TO901317)-treated sites display both normal quantities of secreted lipid (Panel E) and normal organization of lamellar bilayers (Panels B&E, arrows). Decreased lamellar body secretion is indicated by paucity of lamellae at stratum granulosum (SG)-SC interface (Panel C, asterisks). As a result of decreased secretion, abundant lamellar body contents remain entombed in corneocytes (Panel D, arrows). A, B, D, E, ruthenium tetroxide post-fixation; C, osmium tetroxide post-fixative. Mag bars (A) = 0.2 μm (B) = 0.1 μm. (C) = 0.5 μm; (D) = 0.1 μm; (E) = 0.1 μm.
Figure 4
Figure 4. Topical LXR Ligand Reduces Serine Protease Activity
Serine protease activity, assessed zymographically, in frozen sections of normal+ethanol vehicle (N), Ox+vehicle (V), and Ox+ LXR ligand, TO901317 (TO).
Figure 5
Figure 5. Topical PPAR/LXR Activators Decrease Tissue Eosinophilia and Mast Cells in Ox-AD Mice
Eosinophils were stained in paraffin-embedded with hematoxylin & eosin (Panel A, arrows), while mast cells were stained with toluidine blue. (Panel B, arrows). Panels C&D: Quantitation of tissue eosinophils (C) and mast cells numbers (and degranulated mast cell numbers) per mm2 (D) was performed as described in Methods.
Figure 6
Figure 6. PPARα, β/δ, and LXR Ligands Normalize TH2 Inflammation in Ox-AD Mice
Skin samples and blood were collected as described in Methods for CRTH2 immunostaining (A), CRTH2-positive cell counts (B), serum TARC (C) and IgE level (D). ETOH: Ethanol-treated sites in normal mice, as control for Ox treatment. CRTH2: n=30; TARC: n=6-7; IgE: n=3-5.

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