The Functional And Molecular Mechanism By Which TLR3Induces S100A7to Regulate Keratinocyte Differentiation

The treatment of wounds, burns, and long-term unhealed wounds in the diabetic patients has always been a major problem of medicare. The process of healing after wound includes inflammation, re-epithelization and tissue remodeling etc. Re-epithelization is the most important part among these processes, because epithelialization reduces exposure to infection and granulation tissue hyperplasia. Wound healing is a complex process and a variety of tissues and cells are involved in the precise regulation of wound repair. Among these tissues and cells, keratinocytes, the main sensor in the skin after injury, initiate their specific immune responses to ensure normal wound healing rapidly and effectively.Re-epithelialization is a complex and orderly physiological process, and keratinocyte differentiation play an important regulatory role in this process. Our previous study has shown that TLR3activation in keratinocyte was essential for inflammatory responses after skin injury, and Lin et al has found that wound healing in TLR3-deficient mice was significantly slower than that in wild-type mice. These results indicate that TLR3may play a positive role in the healing process. However, how TLR3regulates the wound healing remains unknown. S100A7is a differentiation-related protein, and its function is as the following:intracellular activation of S100A7may regulate cell differentiation, proliferation, apoptosis and lipid metabolism; or S100A7is released into the extracellular as a chemokine and anti-bacterial protein. However, what’s the correlation of TLR3activation and S100A7expression and what’s role of S100A7in wound helaing remain unknown. In this study we will focus on these two questions.Our results demonstrate that S100A7was highly expressed in mouse wounded skin and significantly induced by Toll-like receptor3ligand(poly(I:C)) in normal human keratinocytes. The induction of S100A7by poly(I:C) was dependent on TLR3and p38MAPK as the siRNA of TLR3and the inhibitors of p38MAPK significantly decreased the expression of S100A7. In addition to S100A7, poly(I:C) induced caspase-1and keratinocyte differentiation marker gene, loricrin. The knockdown of S100A7abrogated the expression of caspase-1and loricrin by poly(I:C). S100A7itself can active p38MAPK and caspase-1to induce loricrin expression. Furthermore, S100A7-induced keratinocyte differentiation via the activation of p63as knockdown of ANp63decreased S100A7-induced loricrin. Furthermore, S100A7accelerated wound hearing by increasing the process of re-epithelialization. Taken together, these data suggest that S100A7may become a potential drug to treat skin wounds. Making the TLR3and S100A7signal transduction pathway in wound healing clear will help to improve wound healing in clinical treatment program.