1. ¹Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, California, USA
2. ²Gene Expression Laboratories, The Salk Institute for Biological Studies, La Jolla, California, USA
3. ³Department of Medicine, University of California San Francisco and VA Medical Center San Francisco, San Francisco, California, USA

Correspondence: Dr Kenneth R. Feingold, VA Medical Center, Metabolism Section (111F), 4150 Clement Street, San Francisco, California 94121, USA. E-mail: kfngld@itsa.ucsf.edu

Received 16 February 2007; Revised 21 May 2007; Accepted 24 June 2007; Published online 23 August 2007.

Abstract

In cultured human keratinocytes or murine epidermis, peroxisome proliferator-activated receptor / (PPAR/) (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 PPAR/ could play an important role in cutaneous homeostasis, we assessed here the skin phenotype of mice deficient in PPAR/. 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 PPAR/^-/- mice. Although basal permeability barrier function was normal, PPAR/ 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, PPAR/ KO mice displayed increased inflammation in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Together, these results further demonstrate that PPAR/ in the epidermis: (1) is required for permeability barrier homeostasis; (2) regulates keratinocyte proliferation; and (3) modulates cutaneous inflammation.