Sumikawa Yasuyuki, Asada Hideo, Hoshino Katsuaki, Azukizawa Hiroaki, Katayama Ichiro, Akira Shizuo, Itami Satoshi
Department of Dermatology, Course of Molecular Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Microbes Infect. 2006 May;8(6):1513-21. doi: 10.1016/j.micinf.2006.01.008. Epub 2006 Apr 7.
The epidermis, which covers the surface of all mammals, serves as a front line of defense against the invasion of pathogenic microbes and acts as a crucial site for innate immune responses. Various antimicrobial molecules are expressed not only on the surfaces of monocytes but also on epithelial cells. beta-Defensins, a family of antimicrobial peptides, are produced by several types of epithelial cells, including keratinocytes. However, the induction pathways for beta-defensins in keratinocytes are not fully understood. We hypothesized that bacterial components would trigger the expression of beta-defensins in keratinocytes through a toll-like receptor (TLR)-MyD88 signaling pathway that plays important roles in innate immunity. Production of TNF-alpha and IL-1 alpha following stimulation with lipopolysaccharide or bacterial lipopeptides was completely abolished in TLR2&TLR4-doubly deficient keratinocytes and in MyD88-deficient keratinocytes. Expression of murine beta-defensin was upregulated by bacterial lipopeptides in wild-type keratinocytes, while it was attenuated in TLR2-deficient keratinocytes. To evaluate the in vivo role of TLRs in keratinocytes, we inoculated Staphylococcus aureus into the tail skin from TLR2-deficient mice that had been grafted on the dorsal skin of syngeneic mice. The grafted skin from TLR2-deficient mice resulted in erosion. These studies strongly suggest that the TLR2-MyD88-dependent pathway in keratinocytes is essential for antimicrobial activity in vivo.
覆盖所有哺乳动物体表的表皮，是抵御病原微生物入侵的第一道防线，也是先天性免疫反应的关键部位。多种抗菌分子不仅在单核细胞表面表达，也在上皮细胞表面表达。β-防御素是一类抗菌肽，由包括角质形成细胞在内的多种上皮细胞产生。然而，角质形成细胞中β-防御素的诱导途径尚未完全明确。我们推测细菌成分会通过Toll样受体（TLR）-MyD88信号通路触发角质形成细胞中β-防御素的表达，该信号通路在先天性免疫中起重要作用。在用脂多糖或细菌脂肽刺激后，TLR2和TLR4双缺陷角质形成细胞以及MyD88缺陷角质形成细胞中TNF-α和IL-1α的产生完全被消除。野生型角质形成细胞中，细菌脂肽可上调小鼠β-防御素的表达，而在TLR2缺陷角质形成细胞中表达减弱。为评估TLR在角质形成细胞中的体内作用，我们将金黄色葡萄球菌接种到移植于同基因小鼠背部皮肤的TLR2缺陷小鼠的尾部皮肤。TLR2缺陷小鼠的移植皮肤出现糜烂。这些研究强烈表明，角质形成细胞中TLR2-MyD88依赖性途径对体内抗菌活性至关重要。
