Michalik L, Feige J N, Gelman L, Pedrazzini T, Keller H, Desvergne B, Wahli W
Center for Integrative Genomics, National Center of Competence in Research Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland.
Mol Endocrinol. 2005 Sep;19(9):2335-48. doi: 10.1210/me.2005-0068. Epub 2005 May 12.
Many nuclear hormone receptors are involved in the regulation of skin homeostasis. However, their role in the epithelial compartment of the skin in stress situations, such as skin healing, has not been addressed yet. The healing of a skin wound after an injury involves three major cell types: immune cells, which are recruited to the wound bed; dermal fibroblasts; and epidermal and hair follicle keratinocytes. Our previous studies have revealed important but nonredundant roles of PPARalpha and beta/delta in the reparation of the skin after a mechanical injury in the adult mouse. However, the mesenchymal or epithelial cellular compartment in which PPARalpha and beta/delta play a role could not be determined in the null mice used, which have a germ line PPAR gene invalidation. In the present work, the role of PPARalpha was studied in keratinocytes, using transgenic mice that express a PPARalpha mutant with dominant-negative (dn) activity specifically in keratinocytes. This dn PPARalpha lacks the last 13 C terminus amino acids, binds to a PPARalpha agonist, but is unable to release the nuclear receptor corepressor and to recruit the coactivator p300. When selectively expressed in keratinocytes of transgenic mice, dn PPARalphaDelta13 causes a delay in the healing of skin wounds, accompanied by an exacerbated inflammation. This phenotype, which is similar to that observed in PPARalpha null mice, strongly suggests that during skin healing, PPARalpha is required in keratinocytes rather than in other cell types.
许多核激素受体参与皮肤稳态的调节。然而，它们在皮肤应激情况下（如皮肤愈合）上皮部分的作用尚未得到研究。皮肤受伤后的伤口愈合涉及三种主要细胞类型：被招募到伤口床的免疫细胞、真皮成纤维细胞以及表皮和毛囊角质形成细胞。我们之前的研究揭示了PPARα和β/δ在成年小鼠机械损伤后皮肤修复中具有重要但非冗余的作用。然而，在所使用的种系PPAR基因无效的基因敲除小鼠中，无法确定PPARα和β/δ发挥作用的间充质或上皮细胞区室。在本研究中，利用在角质形成细胞中特异性表达具有显性负性（dn）活性的PPARα突变体的转基因小鼠，研究了PPARα在角质形成细胞中的作用。这种dn PPARα缺少最后13个C末端氨基酸，能与PPARα激动剂结合，但无法释放核受体共抑制因子，也不能招募共激活因子p300。当在转基因小鼠的角质形成细胞中选择性表达时，dn PPARαΔ13会导致皮肤伤口愈合延迟，并伴有炎症加剧。这种表型与在PPARα基因敲除小鼠中观察到的相似，强烈表明在皮肤愈合过程中，角质形成细胞而非其他细胞类型需要PPARα。
