To gain insight into the molecular mechanisms underlying cutaneous wound repair, we performed a large scale screen to identify novel injury-regulated genes. Here we show a strong up-regulation of the RNA and protein levels of the two Ca 2؉ -binding proteins S100A8 and S100A9 in the hyperthickened epidermis of acute murine and human wounds and of human ulcers. Furthermore, both genes were expressed by inflammatory cells in the wound. The increased expression of S100A8 and S100A9 in wound keratinocytes is most likely related to the activated state of the keratinocytes and not secondary to the inflammation of the skin, since we also found up-regulation of S100A8 and S100A9 in the epidermis of activin-overexpressing mice, which develop a hyperproliferative and abnormally differentiated epidermis in the absence of inflammation. Furthermore, S100A8 and S100A9 expression was found to be associated with partially differentiated keratinocytes in vitro. Using confocal microscopy, both proteins were shown to be at least partially associated with the keratin cytoskeleton. In addition, cultured keratinocytes efficiently secreted the S100A8/A9 dimer. These results together with previously published data suggest that S100A8 and S100A9 are novel players in wound repair, where they might be involved in the reorganization of the keratin cytoskeleton in the wounded epidermis, in the chemoattraction of inflammatory cells, and/or in the defense against microorganisms.After cutaneous injury, a series of biological events takes place that aims at the reconstruction of the damaged skin. Among them are the migration, proliferation, and differentiation of inflammatory, epithelial, and mesenchymal cells. These cells exert specific functions in a temporally and spatially coordinated manner such as the removal of irreversibly destructed tissue, the deposition of new extracellular matrix, and the reestablishment of the cutaneous barrier (1, 2). These processes are well described at the histological level, but little is known about their molecular basis.To gain insight into the molecular mechanisms that underlie the repair process, we performed a large scale subtractive hybridization screen to systematically identify genes that are differentially expressed in injured compared with normal skin. To minimize the risk of detecting differences in gene expression levels due to changes in cellular composition rather than to transcriptional regulation, we compared normal skin with early (24 h) wounds, because only minor changes in cell type composition occur during the initial wound healing period.One of the cDNA clones that we obtained encodes the murine S100A8 protein (also known as calgranulin A, MRP8, leukocyte protein L1, or cytokine CP-10). S100 proteins are intracellular Ca 2ϩ -binding and Ca 2ϩ -modulated proteins that form antiparallel noncovalently linked dimers in solution and play a role in various Ca 2ϩ -mediated cellular functions including cell growth and differentiation, energy metabolism, cytoskeletalmembrane interactions; some of th...

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Cone dystrophies are genetic diseases characterized by loss of cone photoreceptor function and severe impairment of daylight vision. Loss of function is accompanied by a progressive degeneration of cones limiting potential therapeutic interventions. In this study we combined microarray-based gene-expression analysis with electroretinography and immunohistochemistry to characterize the pathological processes in the cone photoreceptor function loss 1 (cpfl1) mouse model. The cpfl1-mouse is a naturally arising mouse mutant with a loss-of-function mutation in the cone-specific Pde6c gene. Cpfl1-mice displayed normal rod-specific light responses while cone-specific responses were strongly diminished. Despite the lack of a general retinal degeneration, the cone-specific functional defect resulted in a marked activation of GFAP, a hallmark of Müller-cell gliosis. Microarray-based network-analysis confirmed activation of Müller-glia-specific transcripts. Unexpectedly, we found up-regulation of the cytokine LIF and the anti-apoptotic transcription factor STAT3 in cpfl1 cone photoreceptors. We postulate that STAT3-related pathways are induced in cpfl1 cone photoreceptors to counteract degeneration.