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小胶质细胞糖皮质激素受体通过 TLR9 激活导致中脑多巴胺神经元变性。

TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons.

机构信息

Institute of Biology Paris Seine, Gene Regulation and Adaptive Behaviors Team, Department of Neuroscience Paris Seine, Sorbonne Université, CNRS UMR 8246 & INSERM U1130, 9 Quai Saint Bernard, F-75005, Paris, France.

CEA, DRF, Institut François Jacob, Neurodegenerative Diseases Laboratory, Molecular Imaging Research Center (MIRCen), CNRS, CEA, Université Paris-Sud, Université Paris-Saclay (UMR9199), F-92265, Fontenay-aux-Roses, France.

出版信息

Nat Commun. 2018 Jun 22;9(1):2450. doi: 10.1038/s41467-018-04569-y.

DOI:10.1038/s41467-018-04569-y
PMID:29934589
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6015079/
Abstract

Inflammation is a characteristic feature of Parkinson's disease (PD). We examined the role of TLR9 and its regulation by glucocorticoid receptors (GRs) in degeneration of substantia nigra dopamine neurons (DNs). TLR9 agonist, CpG-ODN, induced DN degeneration in mice lacking GR in microglia but not in controls. TLR9 deletion reduced DN loss in neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. GR regulates TLR9 activation during MPTP neurotoxicity as TLR9 antagonist suppressed increased DN loss in microglia/macrophage GR mutant mice. GR absence in microglia enhanced TLR9 translocation to endolysosomes and facilitated its cleavage leading to pro-inflammatory gene expression. GR-dependent TLR9 activation also triggered DN loss following intranigral injection of mitochondrial DNA. Finally, microglial GR sensitivity to A53T-alpha-synuclein induced DN degeneration as well as decreased microglial GR expression observed in SN of PD brain samples, all suggest that reduced microglial GR activity in SN can stimulate TLR9 activation and DN loss in PD pathology.

摘要

炎症是帕金森病 (PD) 的一个特征。我们研究了 TLR9 的作用及其受糖皮质激素受体 (GRs) 的调节在黑质多巴胺神经元 (DNs) 变性中的作用。TLR9 激动剂 CpG-ODN 在缺乏小胶质细胞中 GR 的小鼠中诱导 DN 变性，但在对照组中没有诱导。TLR9 缺失减少了神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的 PD 小鼠模型中的 DN 丢失。GR 在 MPTP 神经毒性过程中调节 TLR9 的激活，因为 TLR9 拮抗剂抑制了微胶质细胞/巨噬细胞 GR 突变小鼠中 DN 丢失的增加。GR 在小胶质细胞中的缺失增强了 TLR9 向内溶酶体的易位，并促进其切割，导致促炎基因的表达。GR 依赖性 TLR9 激活也会导致核内注射线粒体 DNA 后 DN 丢失。最后，小胶质细胞 GR 对 A53T-α-突触核蛋白诱导的 DN 变性的敏感性，以及 PD 脑样本 SN 中观察到的小胶质细胞 GR 表达减少，都表明 SN 中小胶质细胞 GR 活性的降低可以刺激 TLR9 的激活和 PD 病理中的 DN 丢失。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/6f8198059d92/41467_2018_4569_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/db24b129522c/41467_2018_4569_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/1095294c83ae/41467_2018_4569_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/408301eb3096/41467_2018_4569_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/64159ab14bdc/41467_2018_4569_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/f5590f78f3f8/41467_2018_4569_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/babc11464673/41467_2018_4569_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/16ee35cdca86/41467_2018_4569_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/910db465b688/41467_2018_4569_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/6f8198059d92/41467_2018_4569_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/db24b129522c/41467_2018_4569_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/1095294c83ae/41467_2018_4569_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/408301eb3096/41467_2018_4569_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/64159ab14bdc/41467_2018_4569_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/f5590f78f3f8/41467_2018_4569_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/babc11464673/41467_2018_4569_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/16ee35cdca86/41467_2018_4569_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/910db465b688/41467_2018_4569_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d559/6015079/6f8198059d92/41467_2018_4569_Fig9_HTML.jpg

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