Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling
Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling
复制标题
DOI：
10.1172/jci28115
复制
发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Schaller, Martin
中科院分区：
文献类型：
--
作者：
Weindl, Guenther;Naglik, Julian R.;Schaller, Martin
哺乳动物TLR是先天免疫系统的中心介质，其指导细胞进行先天和适应性反应以清除微生物感染。在这里，我们证明，人类上皮TLR 4直接保护口腔粘膜真菌感染通过多形核白细胞（PMNs）介导的过程。在口腔念珠菌病的体外上皮模型中，真菌病原体白色念珠菌诱导了化学吸引和促炎细胞因子反应，但未能直接调节编码TLR的基因的表达。然而，除了中性粒细胞的白色念珠菌感染的模型强烈上调细胞质和细胞表面的上皮细胞TLR 4的表达，这直接与保护真菌入侵和细胞损伤。C.通过加入TLR 4特异性中和抗体和使用RNA干扰敲低TLR 4，即使在存在PMN的情况下，也可以恢复白念珠菌的侵袭和细胞损伤，证明上皮TLR 4在保护过程中的直接作用。此外，用TNF-α特异性中和抗体治疗。导致TLR 4表达的强烈降低，伴随着上皮细胞损伤和真菌侵袭的增加。据我们所知，这是第一次描述这种PMN依赖性，TLR 4介导的上皮表面保护机制，这可能会提供重要的见解如何管理和控制微生物感染的口腔粘膜。
Mammalian TLRs are central mediators of the innate immune system that instruct cells of the innate and adaptive response to clear microbial infections. Here, we demonstrate that human epithehal TLR4 directly protected the oral mucosa from fungal infection via a process mediated by polymorphonuclear leukocytes (PMNs). In an in vitro epithelial model of oral candidiasis, the fungal pathogen Candida albicans induced a chemoattractive and proinflammatory cytokine response but failed to directly modulate the expression of genes encoding TLRs. However, the addition of PMNs to the C albicans-infected model strongly upregulated cytoplasmic and cell-surface epithelial TLR4 expression, which correlated directly with protection against fungal invasion and cell injury. C. albicans invasion and cell injury was restored by the addition of TLR4-specific neutralizing antibodies and knockdown of TLR4 using RNA interference, even in the presence of PMNs, demonstrating the direct role of epithelial TLR4 in the protective process. Furthermore, treatment with neutralizing antibodies specific for TNF-alpha. resulted in strongly reduced TLR4 expression accompanied by augmented epithelial cell damage and fungal invasion. To our knowledge, this is the first description of such a PMN-dependent, TLR4-mediated protective mechanism at epithelial surfaces, which may provide significant insights into how microbial infections are managed and controlled in the oral mucosa.