Regulation of epithelial–mesenchymal IL-1 signaling by PPARβ/δ is essential for skin homeostasis and wound healing

Skin morphogenesis, maintenance, and healing after wounding require complex epithelial–mesenchymal interactions. In this study, we show that for skin homeostasis, interleukin-1 (IL-1) produced by keratinocytes activates peroxisome proliferator–activated receptor β/δ (PPARβ/δ) expression in underlying fibroblasts, which in turn inhibits the mitotic activity of keratinocytes via inhibition of the IL-1 signaling pathway. In fact, PPARβ/δ stimulates production of the secreted IL-1 receptor antagonist, which leads to an autocrine decrease in IL-1 signaling pathways and consequently decreases production of secreted mitogenic factors by the fibroblasts. This fibroblast PPARβ/δ regulation of the IL-1 signaling is required for proper wound healing and can regulate tumor as well as normal human keratinocyte cell proliferation. Together, these findings provide evidence for a novel homeostatic control of keratinocyte proliferation and differentiation mediated via PPARβ/δ regulation in dermal fibroblasts of IL-1 signaling. Given the ubiquitous expression of PPARβ/δ, other epithelial–mesenchymal interactions may also be regulated in a similar manner

Functional roles of transforming growth factor activated Kinase-1 (TAK1) in skin wound healing

Healing wound and maintaining new skin growth requires complex interactions of the epithelium and mesenchyme purportedly mediated by growth factors and cytokines. We show here that during wound healing, TAK1 activates von Hippel-Lindau tumor suppressor (pVHL) expression in keratinocytes which, in turn, represses the expression of PDGF-B and, integrins beta1 and beta5 via inhibition of the Sp1-mediated transcription. The reduced production of PDGF-B leads to a paracrine decrease in expression of hepatocyte growth factor (HGF) in the underlying fibroblasts, as well as reduced epidermal proliferation. This TAK1 regulation of the dual PDGF/HGF paracrine signaling system can regulate keratinocyte cell proliferation and is required for proper wound healing. Strikingly, TAK1 deficiency enhances cell migration. TAK1-deficient keratinocytes displayed lamellipodia formation with distinct microspikes protrusions, which was associated with an elevated expression of integrins beta1 and beta5, and sustained activation of cdc42, Rac1 and RhoA. Our findings provide evidence for a novel homeostatic control of keratinocyte proliferation and migration, mediated via TAK1 regulation of pVHL. Dysfunctional regulation of TAK1 may contribute to the pathology of chronic inflammatory wounds and psoriasis.DOCTOR OF PHILOSOPHY (SBS