Deficiency of PPARbeta/delta in the epidermis results in defective cutaneous permeability barrier homeostasis and increased inflammation.

Abstract

In cultured human keratinocytes or murine epidermis, peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) (NR1C2) activators (1) stimulate keratinocyte differentiation; (2) decrease keratinocyte proliferation; (3) accelerate permeability barrier repair; (4) increase epidermal lipid synthesis; and (5) reduce cutaneous inflammation. Since these results suggest that PPARbeta/delta could play an important role in cutaneous homeostasis, we assessed here the skin phenotype of mice deficient in PPARbeta/delta. Gross cutaneous abnormalities were not evident, and both stratum corneum (SC) skin hydration and surface pH were normal. However, the epidermis was thickened and proliferating cell nuclear antigen (PCNA) staining was increased, indicating increased cell proliferation. No change in apoptosis was observed but the expression of differentiation markers, such as filaggrin, involucrin, and loricrin, was slightly increased in PPARbeta/delta(-/-) mice. Although basal permeability barrier function was normal, PPARbeta/delta knockout (KO) mice show a significant delay in barrier recovery rates following acute barrier disruption by either acetone treatment or tape-stripping. Delayed barrier recovery correlated with decreased production and secretion of lamellar bodies (LBs), and with reduced numbers of extracellular lamellar membranes in the SC. Finally, PPARbeta/delta KO mice displayed increased inflammation in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Together, these results further demonstrate that PPARbeta/delta in the epidermis: (1) is required for permeability barrier homeostasis; (2) regulates keratinocyte proliferation; and (3) modulates cutaneous inflammation.

• Authors: 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: The Journal of investigative dermatology (J Invest Dermatol) Vol. 128 Issue 2 Pg. 370-7 (Feb 2008) ISSN: 1523-1747 [Electronic] United States
• PMID: 17713572 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• FLG protein, human
• Filaggrin Proteins
• PPAR gamma
• PPAR-beta

Topics

• Acute Disease
• Animals
• Cell Division (physiology)
• Dermatitis (immunology, metabolism, pathology)
• Epidermis (injuries, metabolism, pathology)
• Filaggrin Proteins
• Homeostasis (physiology)
• Keratinocytes (cytology, physiology)
• Male
• Mice
• Mice, Inbred Strains
• Mice, Knockout
• PPAR gamma (chemistry, genetics, metabolism)
• PPAR-beta (chemistry, genetics, metabolism)
• Permeability
• Protein Structure, Tertiary
• Wound Healing (immunology)