Regulation of skin innate immunity by epidermal differentiation

表皮角质形成细胞分化形成多层表皮，是机体与外界环境之间的主要屏障。由于表皮不断暴露于各种微生物病原体中，其抵抗微生物病原体的功能至关重要。Poly （I:C）处理诱导MIP-1？正常人角质形成细胞的生成。IFN-?的中和抗体显著抑制poly （I:C）诱导的MIP-1？产量表明MIP-1?？生产是通过IFN-？干扰素- ?引发TLR3表达增强和MIP-1？聚（I:C）处理的角质形成细胞的生产。这表明IFN-？增强TLR3的表达，增强角质形成细胞对poly （I:C）的反应，从而导致MIP-1的产生增加。因此，正常的人角质形成细胞产生MIP-1？通过TLR3响应dsRNA，这种产生受IFN-？? ?。免疫组化分析显示正常人皮肤上表皮表达？-防御素（hBD） 1-3和LL37。转染ASK1-ΔN可显著增强正常人角质形成细胞中hBD 1-3和LL37的表达。此外，一种p38抑制剂消除了这种诱导，表明ASK1-p38调节hBD1-3和LL37的表达。此外，ASK1-p38还调节角质形成细胞中toll样受体（TLR） 2的表达。因此，ASK1-p38通过在表皮分化过程中形成由hBDs、LL37和TLR2组成的免疫屏障来调节皮肤的先天免疫。皮肤伤口愈合是抵抗微生物病原体的必要条件，角质细胞迁移是皮肤伤口愈合的重要步骤。由于LL-37在皮肤伤口部位上调，LL-37可能会诱导角质细胞迁移。在本研究中，我们发现LL-37通过hb - egf介导的EGFR转激活诱导角质形成细胞迁移。本研究强烈提示LL-37通过诱导角质细胞迁移来关闭皮肤伤口。

Epidermal keratinocytes differentiate and form a multilayered epidermis, which is the primary barrier between the body and the outer environment. As the epidermis is constantly exposed to a variety of microbial pathogens, its function of resisting microbial pathogens is vital.Poly (I:C) treatment induced MIP-1? production in normal human keratinocytes. A neutralizing antibody for IFN-? significantly inhibited the poly (I:C)-induced MIP-1? production indicating that MIP-1??production is via IFN-?. IFN-? priming enhanced TLR3 expression and MIP-1? production in poly (I:C)-treated keratinocytes. This suggests that IFN-? enhanced the TLR3 expression and reinforced the response of keratinocytes to poly (I:C), which resulted in an increase in MIP-1??production. Therfore, normal human keratinocytes produce MIP-1? in response to dsRNA via TLR3, and this production is regulated by IFN-? ??.Immunohistochemical analysis revealed that the upper epidermis of normal human skin expresses ?-defensins (hBD) 1-3 and LL37. Transfection of ASK1-ΔN significantly enhanced the expression of hBD 1-3 and LL37 in normal human keratinocytes. In addition, a p38 inhibitor abolished this induction, indicating that ASK1-p38 regulates the expression of hBD1-3 and LL37. Furthermore, ASK1-p38 also regulated the expression of Toll-like receptor (TLR) 2 in keratinocytes. Therefore, ASK1-p38 regulates the innate immunity of the skin by forming an immune barrier consisting of hBDs, LL37, and TLR2 during epidermal differentiation.Skin wound closure is essential for resistance against microbial pathogens, and keratinocyte migration is an important step in skin wound healing. Since LL-37 is upregulated at skin wound sites, LL-37 may induce keratinocyte migration. In this study, we found that LL-37 induced keratinocyte migration via HB-EGF-mediated transactivation of EGFR. This study strongly suggests that LL-37 closes the skin wound by induction of keratinocyte migration.