Abstract：
Parkinson\'s disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16 S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16 S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.
摘要：
帕金森病(Parkinson’sdisease,PD)是一种发病机制尚不清楚的慢性神经退行性疾病,涉及神经炎症和肠道微生物菌群失调。细胞间粘附分子-1(ICAM-1),炎症标记物,参与多巴胺能神经元损伤期间的神经炎症。然而,ICAM-1在PD中的明确作用机制尚未阐明.我们通过腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）建立了亚急性PD小鼠模型，并观察了小鼠的运动症状和胃肠功能障碍。免疫荧光用于检查多巴胺能神经元的存活，小胶质细胞和星形胶质细胞标志物的表达，和肠道紧密连接相关蛋白。然后，我们使用16SrRNA测序来鉴定微生物群的改变。我们的发现表明，ICAM-1特异性抗体（Ab）治疗缓解了行为缺陷，胃肠功能障碍,MPTP诱导的PD小鼠的多巴胺能神经元死亡。进一步的机制研究表明，ICAM-1Ab可能通过抑制黑质中星形胶质细胞和小胶质细胞的激活以及减轻结肠屏障损伤和肠道炎症来抑制神经炎症。此外，16SrRNA测序显示，细菌厚壁菌的相对丰度，梭菌,在PD小鼠中，Lachnospileaceae升高。然而,ICAM-1Ab治疗改善了肠道微生物群中MPTP诱导的疾病。总的来说，我们得出结论，抑制ICAM-1可能导致炎症的显着减少和恢复肠道微生物群落，从而改善DA神经元的损伤。
