Department of Pathology, Section of Neuropathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
J Innate Immun. 2017;9(5):456-463. doi: 10.1159/000477990. Epub 2017 Jun 27.
Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract.
We immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation.
We showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation.
These findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.
α-突触核蛋白（αS）是一种与帕金森病（PD）相关的神经细胞蛋白。αS 在肠神经系统（ENS）内的积累及其从肠道向大脑的转运与 PD 的发病机制和进展有关。αS 在人类中没有已知的功能，其在 ENS 中积累的原因尚不清楚。最近在啮齿动物中进行的几项研究将 αS 与中枢神经系统中免疫细胞的激活联系起来。我们假设 ENS 中的 αS 可能在人类胃肠道（GI）道的先天免疫防御中发挥作用。
我们对有明确胃和十二指肠炎症的儿童和感染诺如病毒的肠移植受者的内镜活检进行了 αS 的免疫染色。为了确定 αS 是否具有免疫调节活性，我们检查了人 αS 是否诱导白细胞迁移和树突状细胞成熟。
我们表明，儿科患者上胃肠道的肠神经突中 αS 的表达与肠壁的急性和慢性炎症程度呈正相关。在密切监测感染的肠移植受者中，在诺如病毒感染期间诱导了 αS 的表达。我们还证明，单体和寡聚体 αS 均具有强大的趋化活性，导致中性粒细胞和单核细胞的迁移依赖于整合素亚基 CD11b 的存在，并且这两种形式的 αS 均刺激树突状细胞成熟。
这些发现强烈表明，αS 在人类 ENS 中表达以指导肠道炎症，并提示常见的胃肠道感染与 PD 的发病机制有关。
