Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA; Department of Anatomy, College of Medicine and Health Science, United Arab Emirates University, Al Ain, PO Box 17666, United Arab Emirates.
Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA; Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65201, USA; Veterans Affairs Health Care System, Iowa City, IA 52242, USA; Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65201, USA.
Int Immunopharmacol. 2020 Jun;83:106441. doi: 10.1016/j.intimp.2020.106441. Epub 2020 Apr 4.
Neuroinflammation plays an active role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease (PD). Earlier studies from this laboratory showed that glia maturation factor (GMF), a proinflammatory mediator; is up-regulated in the brain in neurodegenerative diseases and that deficiency of GMF showed decreased production of IL-1β and improved behavioral abnormalities in mouse model of PD. However, the mechanisms linking GMF and dopaminergic neuronal death have not been completely explored. In the present study, we have investigated the expression of NLRP3 inflammasome and caspase-1 in the substantia nigra (SN) of human PD and non-PD brains by immunohistochemistry. Wild-type (WT) and GMF (GMF knock-out) mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP) and the brains were isolated for neurochemical and morphological examinations. NLRP3 and caspase-1 positive cells were found significantly increased in PD when compared to non-PD control brains. Moreover, GMF co-localized with α-Synuclein within reactive astrocytes in the midbrain of PD. Mice treated with MPTP exhibit glial activation-induced inflammation, and nigrostriatal dopaminergic neurodegeneration. Interestingly, increased expression of the inflammasome components in astrocytes and microglia observed in the SN of MPTP-treated WT mice were significantly reduced in GMF mice. Additionally, we show that NLRP3 activation in microglia leads to translocation of GMF and NLRP3 to the mitochondria. We conclude that downregulation of GMF may have beneficial effects in prevention of PD by modulating the cytotoxic functions of microglia and astrocytes through reduced activation of the NLRP3 inflammasome; a major contributor of neuroinflammation in the CNS.
神经炎症在几种神经退行性疾病的发病机制中起积极作用，包括帕金森病 (PD)。本实验室的早期研究表明，神经胶质细胞成熟因子 (GMF)，一种促炎介质；在神经退行性疾病的大脑中上调，GMF 缺乏显示 IL-1β 的产生减少，并改善 PD 小鼠模型的行为异常。然而，将 GMF 与多巴胺能神经元死亡联系起来的机制尚未完全探索。在本研究中，我们通过免疫组织化学研究了 NLRP3 炎性小体和半胱天冬酶-1 在人 PD 和非 PD 大脑中的黑质 (SN) 中的表达。野生型 (WT) 和 GMF (GMF 敲除) 小鼠用 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 处理，并分离大脑进行神经化学和形态学检查。与非 PD 对照大脑相比，PD 中的 NLRP3 和半胱天冬酶-1 阳性细胞明显增加。此外，GMF 与 PD 中中脑反应性星形胶质细胞内的 α-突触核蛋白共定位。用 MPTP 处理的小鼠表现出胶质细胞激活诱导的炎症和黑质纹状体多巴胺能神经退行性变。有趣的是，在 MPTP 处理的 WT 小鼠 SN 中观察到的星形胶质细胞和小胶质细胞中炎性小体成分的表达增加在 GMF 小鼠中显著降低。此外，我们表明，小胶质细胞中 NLRP3 的激活导致 GMF 和 NLRP3 向线粒体的易位。我们得出结论，GMF 的下调可能通过减少 NLRP3 炎性小体的激活来调节小胶质细胞和星形胶质细胞的细胞毒性功能，从而对预防 PD 产生有益影响；NLRP3 炎性小体是 CNS 中神经炎症的主要贡献者。
