EGFR/MAPK信号通路调控角质形成细胞抗原提呈和创面免疫炎症反应分子机制的研究

创面炎症微环境是造成慢性创面难愈合的重要原因。表皮角质形成细胞在炎症、感染时开启抗原提呈细胞功能，激活T细胞，引发适应性免疫反应，参与炎症微环境的形成。但角质形成细胞抗原提呈功能在慢性创面愈合中的作用及调控其抗原提呈功能的分子机制尚不清楚。EGFR和MAPK抑制剂在抗癌时引起皮疹，提示EGFR/MAPK信号通路参与皮肤炎症反应。我们前期研究发现阻断该信号通路能在体外和体内促进角质形成细胞表达抗原提呈相关基因、摄取荧光抗原和抑制创面修复。本项目拟利用细胞模型、创面模型、EGFR敲除小鼠、通路阻断剂、高通量测序等研究EGFR/MAPK信号通路对角质形成细胞的抗原提呈相关基因的表达、抗原提呈过程、激活T细胞、创面炎症反应和创面愈合质量的作用及机制。该研究将破译角质形成细胞对创面炎症反应的作用及其抗原提呈功能的分子机制，为改善慢性创面愈合质量及防治皮肤免疫炎症性疾病提供新途径和思路。

Wound inflammatory microenvironments contribute to the chronic wound healing. Under the inflammatory or infectious conditions, epidermal keratinocytes can function as antigen-presenting cells to activate T cells and initiate adaptive immune responses, constituting the inflammatory microenvironments. However, the roles of antigen-presenting functions of keratinocytes in the chronic wound healing and the molecular mechanisms of regulating the antigen-presenting functions of keratinocytes remain unclear. EGFR and MAPK inhibitors can cause skin rashes when used to treat cancers, indicating that the EGFR/MAPK signaling pathway may be associated with skin inflammatory responses. Our previous studies show that inhibiting this signaling pathway can increase the expression of antigen presentation-associated genes, fluorescent antigen uptake in keratinocytes in vitro and in vivo and impair the wound healing. By using cellular models, wound models, EGFR knockout mice, signaling pathway inhibitors, and high-throughput sequencing, the present study aims to investigate the roles and mechanisms of the EGFR/MAPK signaling pathway in regulating the expression of the antigen-presentation-associated genes in keratinocytes, antigen presentation process, and activation of T cells, wound inflammation, and wound healing. This study will discover the contribution of keratinocytes to wound inflammation and the molecular mechanisms underlying their antigen-presenting functions, and will offer new strategies and ideas for improving chronic wound healing as well as preventing and curing skin inflammatory diseases.