Toll-like Receptors in the Intestinal Epithelium: Receptors of Survival or Death or Both?

肠上皮中的 Toll 样受体：生存或死亡或两者兼而有之的受体？

• 批准号: 5356696
• 负责人: Professorin Dr. Elke Cario
• 金额: --
• 依托单位: Klinik für Gastroenterologie und Hepatologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2003-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5356696?language=en
• 关键词: Toll; like; Receptors; Intestinal; Epithelium

The intestinal epithelium serves as an essential defensive barrier of the mucosal immune system that forms a bipolar interface between the diverse populations of microbes of the lumen and subjacent immune cells present in the lamina propria. Intestinal epithelial cells (IEC) express Toll-like receptors (TLR) as pattern recognition receptors at their apical pole - poised to recognize microbial "pathogen-associated molecular patterns" (PAMPs) as "non-self" and to rapidly initiate innate immune responses. Lumenal PAMPs play a central role in initiation and perpetuation of inflammatory bowel disease (IBD). Recent studies have demonstrated that intestinal epithelial TLR expression is differentially altered in IBD. However, so far, very little is known, about the complex recognition mechanisms and functional immune consequences of TLRs through which the intestinal epithelium constantly interacts with PAMPs. Parallel activation of intestinal epithelial pro- and anti-apoptosis reflects an essential mechanism of mucosal immune defense which appears to be severely imbalanced in IBD. It remains elusive whether PAMP-induced activation of TLRs may mediate apoptosis in IEC. Thus, the aim of this research project is to characterize the potential checkpoint function of TLRs and interacting signaling cascades under physiological and pathophysiological conditions - distinctly triggering either pro- or anti-apoptosis in IEC in response to specific PAMPs in vitro and in vivo. Long-term goal is to comprehend the pathogenetic role of intestinal epithelial TLR dysregulation in IBD and to develop new therapeutic strategies of modulation of immune dysfunction.

肠上皮作为粘膜免疫系统的基本防御屏障，其在腔的不同微生物群和存在于固有层中的亚粘膜免疫细胞之间形成双极界面。肠上皮细胞（IEC）在其顶端表达Toll样受体（TLR）作为模式识别受体-准备将微生物"病原体相关分子模式"（PAMP）识别为"非自身"并快速启动先天免疫应答。管腔PAMPs在炎症性肠病（IBD）的发生和持续中起核心作用。最近的研究表明，肠上皮细胞TLR的表达在IBD中发生了差异性改变。然而，到目前为止，人们对TLR的复杂识别机制和功能性免疫后果知之甚少，肠上皮通过TLR不断与PAMP相互作用。肠上皮细胞促凋亡和抗凋亡的平行激活反映了粘膜免疫防御的基本机制，该机制在IBD中似乎严重失衡。PAMP诱导的TLRs激活是否可能介导IEC的凋亡仍是一个谜。因此，本研究项目的目的是表征TLR的潜在检查点功能以及在生理和病理生理条件下相互作用的信号级联-在体外和体内响应于特定PAMP而在IEC中明显触发促凋亡或抗凋亡。长期目标是了解肠上皮TLR失调在IBD发病中的作用，并开发新的调节免疫功能障碍的治疗策略。