The anti-apoptotic role of PPARβ contributes to efficient skin wound healing

PPARα and PPARβ are expressed in the mouse epidermis during fetal development, but their expression progressively disappears after birth. However, the expression of PPARβ is reactivated in adult mice upon proliferative stimuli, such as cutaneous injury. We show here that PPARβ protects keratinocytes from growth factor deprivation, anoikis and TNF-α-induced apoptosis, by modulating both early and late apoptotic events via the Akt1 signaling pathway and DNA fragmentation, respectively. The control mechanisms involve direct transcriptional upregulation of ILK, PDK1, and ICAD-L. In accordance with the anti-apoptotic role of PPARβ observed in vitro, the balance between proliferation and apoptosis is altered in the epidermis of wounded PPARβ mutant mice, with increased keratinocyte proliferation and apoptosis. In addition, primary keratinocytes deleted for PPARβ show defects in both cell-matrix and cell-cell contacts, and impaired cell migration. Together, these results suggest that the delayed wound closure observed in PPARβ mutant mice involves the alteration of several key processes. Finally, comparison of PPARβ and Akt1 knock-out mice reveals many similarities, and suggests that the ability of PPARβ to modulate the Akt1 pathway has significant impact during skin wound healing.