PDF(Pubmed)
Abstract：
The gastrointestinal tract (GI) is the largest immune organ whose function is controlled by a complex network of neurons from the enteric nervous system (ENS) as well as the sympathetic and parasympathetic system. Evolving evidence indicates that cross-communication between gut-innervating neurons and immune cells regulates many essential physiological functions including protection against mucosal infections. We previously demonstrated that following paraoxon treatment, 70 % of the mice were able to survive an oral infection with S. typhimurium, a virulent strain of Salmonella enterica serovar Typhimurium. The present study aims to investigate the effect that rivastigmine, a reversible AChE inhibitor used for the treatment of neurodegenerative diseases, has on the murine immune defenses of the intestinal mucosa. Our findings show that, similar to what is observed with paraoxon, administration of rivastigmine promoted the release of secretory granules from goblet and Paneth cells, resulting in increased mucin layer. Surprisingly, however, and unlike paraoxon, rivastigmine treatment did not affect overall mortality of infected mice. In order to investigate the mechanistic basis for the differential effects observed between paraoxon and rivastigmine, we used multi-color flowcytometric analysis to characterize the immune cell landscape in the intraepithelial (IE) and lamina propria (LP) compartments of intestinal mucosa. Our data indicate that treatment with paraoxon, but not rivastigmine, led to an increase of resident CD3+CD8+ T lymphocytes in the ileal mucosa (epithelium and lamina propria) and CD11b- CD11c+ dendritic cells in the LP. Our findings indicate the requirement for persistent cholinergic pathway engagement to effect a change in the cellular landscape of the mucosal tissue that is necessary for protection against lethal bacterial infections. Moreover, optimal protection requires a collaboration between innate and adaptive mucosal immune responses in the intestine.
摘要：
胃肠道（GI）是最大的免疫器官，其功能受来自肠神经系统（ENS）以及交感神经和副交感神经系统的复杂神经元网络控制。不断发展的证据表明，肠道神经支配神经元和免疫细胞之间的交叉通讯调节许多基本的生理功能，包括防止粘膜感染。我们之前证明了对氧磷治疗后，70%的小鼠能够在鼠伤寒沙门氏菌的口腔感染中存活下来，肠沙门氏菌的强毒株。本研究旨在探讨利伐斯的明的作用，一种可逆的AChE抑制剂，用于治疗神经退行性疾病，对小鼠肠粘膜的免疫防御。我们的研究结果表明,类似于观察到的对氧磷，利伐斯的明的给药促进了杯状和潘氏细胞分泌颗粒的释放，导致粘蛋白层增加。令人惊讶的是,然而,与对氧磷不同，利伐斯的明治疗不影响感染小鼠的总死亡率.为了研究对氧磷和利伐斯的明之间观察到的差异效应的机理基础，我们使用多色流式细胞术分析来表征肠粘膜上皮内（IE）和固有层（LP）隔室中的免疫细胞景观。我们的数据表明对氧磷治疗，但不是利伐斯的明,导致回肠粘膜（上皮和固有层）中驻留的CD3CD8T淋巴细胞和LP中的CD11b-CD11c树突状细胞增加。我们的发现表明，需要持续的胆碱能途径参与以影响粘膜组织细胞景观的变化，这对于防止致命的细菌感染是必需的。此外，最佳的保护需要肠道内先天和适应性粘膜免疫反应的协同作用.
