Deficiency of PPARβ/δ in the Epidermis Results in Defective Cutaneous Permeability Barrier Homeostasis and Increased Inflammation Mao-Qiang Man, Grant.

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Deficiency of PPARβ/δ in the Epidermis Results in Defective Cutaneous Permeability Barrier Homeostasis and Increased Inflammation Mao-Qiang Man, Grant D. Barish, Matthias Schmuth, Debra Crumrine, Yaacov Barak, Sandra Chang, Yan Jiang, Ronald M. Evans, Peter M. Elias, Kenneth R. Feingold Journal of Investigative Dermatology Volume 128, Issue 2, Pages 370-377 (February 2008) DOI: 10.1038/sj.jid.5701026 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Increased epidermal thickness accompanied by increased PCNA staining is observed in PPARβ/δ KO mice. Epidermal thickness of the nucleated cell layer was measured in 100 × hematoxylin & eosin-treated sections. The measurement was taken at every 2cm points along the epidermis. The data are presented as the mean of all measured points (a, n=31 for both groups). The number of PCNA-positive cells was counted on every 2cm segment along the epidermis (b, n=11 for both groups). The data are presented as the mean of all segments counted±SEM. Journal of Investigative Dermatology 2008 128, 370-377DOI: (10.1038/sj.jid.5701026) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Increased inflammatory response to TPA treatment in PPARβ/δ KO mice. A 10μl volume of 0.03%TPA in ethanol was applied to the inner and outer surfaces of the right ears, and the left ears were treated with ethanol alone. Ear thickness was measured before and 18hours after TPA or ethanol applications. Ethanol alone did not alter ear thickness. Data are expressed as mean±SEM (n=11 for each group). Journal of Investigative Dermatology 2008 128, 370-377DOI: (10.1038/sj.jid.5701026) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Permeability barrier recovery is delayed in PPARβ/δ KO mice. Permeability barrier was disrupted with either (a) tape-stripping (b) or acetone. Transepidermal water loss was measured 2 and 4hours after barrier disruption. A significant delay in barrier recovery was observed at both 2 and 4hours in both models in PPARβ/δ KO animals. Data are expressed as percent of barrier recovery and mean±SEM (n=9–12 for wild type, n=10–11 for KO). Journal of Investigative Dermatology 2008 128, 370-377DOI: (10.1038/sj.jid.5701026) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Epidermal PPAR β/δ KO does not alter epidermal lipid synthesis. Full-thickness skin was incubated with 40μCi acetate for 2hours at 37°C, and the incorporation of 14C acetate into lipids was determined as described in Materials and Methods. The total ceramides includes both ceramides and glycoceramides. Data are expressed as nM/g wet epidermal weight/hour) and are mean±SEM (n=5 for each group). Journal of Investigative Dermatology 2008 128, 370-377DOI: (10.1038/sj.jid.5701026) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Secretion of LB contents is decreased, but post-secretory lipid processing is normal in PPARβ/δ KO epidermis. Skin biopsies from 6- to 8-week-old wild-type and PPARβ/δ KO mice were fixed in Karnovsky's fixative overnight, and post-fixed with 0.25% ruthenium tetroxide or 1% aqueous osmium tetroxide. Ultrathin sections were visualized with an electron microscope. Post-secretory processing of secreted LB contents in lamellar membranes (a and b, arrows) begins at the SG–SC interface in both PPARβ/δ KO and wild-type (wt) mice. Decreased quantities of secreted LB contents are apparent in (c) KO (arrowheads) versus (d) wt mice (arrows). (a, b) ruthenium tetroxide post-fixation; (c, d) osmium tetroxide post-fixation. Bar=0.2μm. Journal of Investigative Dermatology 2008 128, 370-377DOI: (10.1038/sj.jid.5701026) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 The number of LB is decreased in PPARβ/δ KO epidermis. Skin samples from both wild-type and PPARβ/δ KO mice were fixed with osmium tetroxide as described in Materials and Methods. (a) There is abundant LB in the SG in wild-type epidermis (arrows). (b) In contrast, there are only a few partially filled LB found in PPARβ/δ KO epidermis (arrows). Bar=2μm. Journal of Investigative Dermatology 2008 128, 370-377DOI: (10.1038/sj.jid.5701026) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions