Viral-like TLR3 induction of cytokine networks and α-synuclein are reduced by complement C3 blockade in mouse brain.
Viral-like TLR3 induction of cytokine networks and α-synuclein are reduced by complement C3 blockade in mouse brain.
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DOI：
10.1038/s41598-023-41240-z
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发表时间：
2023-09-13
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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作者：
炎症过程和机制在神经退行性疾病中起着核心作用。在大脑中，帕金森氏病(PD)和路易体痴呆(LBD)等α-SYN病表现为免疫细胞因子网络激活和病毒双链RNAToll样受体3(TLR3)水平升高。TLR3激活引起的脑部炎症反应也与理解病毒SARS-CoV-2感染导致新冠肺炎后脑相关综合征的致病级联反应有关。在目前的研究中，在dsRNA诱导小鼠局部脑TLR3激活后，在2天后出现急性补体C3反应。一种C3剪接开关反义寡核苷酸，促进非产生的C3mRNA的剪接，阻止下游细胞因子，如IL-6和α-突触核蛋白的变化。这份报告首次证明了α-突触核蛋白的增加发生在补体C3激活的下游。与脑功能障碍、新冠肺炎后综合征和导致帕金森病和腰椎间盘突出症的病理变化相关的是，C3补体阻断时病毒dsRNATLR3的激活进一步揭示了补体系统、炎性细胞因子网络和α-突触核蛋白变化之间的显著相互作用。
Inflammatory processes and mechanisms are of central importance in neurodegenerative diseases. In the brain, α-synucleinopathies such as Parkinson’s disease (PD) and Lewy body dementia (LBD) show immune cytokine network activation and increased toll like receptor 3 (TLR3) levels for viral double-stranded RNA (dsRNA). Brain inflammatory reactions caused by TLR3 activation are also relevant to understand pathogenic cascades by viral SARS-CoV-2 infection causing post- COVID-19 brain-related syndromes. In the current study, following regional brain TLR3 activation induced by dsRNA in mice, an acute complement C3 response was seen at 2 days. A C3 splice-switching antisense oligonucleotide (ASO) that promotes the splicing of a non-productive C3 mRNA, prevented downstream cytokines, such as IL-6, and α-synuclein changes. This report is the first demonstration that α-synuclein increases occur downstream of complement C3 activation. Relevant to brain dysfunction, post-COVID-19 syndromes and pathological changes leading to PD and LBD, viral dsRNA TLR3 activation in the presence of C3 complement blockade further revealed significant interactions between complement systems, inflammatory cytokine networks and α-synuclein changes.
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影响因子：
17.1
作者：
Frere, Justin J.;Serafini, Randal A.;Pryce, Kerri D.;Zazhytska, Marianna;Oishi, Kohei;Golynker, Ilona;Panis, Maryline;Zimering, Jeffrey;Horiuchi, Shu;Hoagland, Daisy A.;Moller, Rasmus;Ruiz, Anne;Kodra, Albana;Overdevest, Jonathan B.;Canoll, Peter D.;Borczuk, Alain C.;Chandar, Vasuretha;Bram, Yaron;Schwartz, Robert;Lomvardas, Stavros;Zachariou, Venetia;Tenoever, Benjamin R.
通讯作者：
Tenoever, Benjamin R.
影响因子：
5.4
作者：
Beatman, Erica L.;Massey, Aaron;Beckham, J. David
通讯作者：
Beckham, J. David
影响因子：
14
作者：
Frontera, Jennifer A.;Boutajangout, Allal;Masurkar, Arjun, V;Betensky, Rebecca A.;Ge, Yulin;Vedvyas, Alok;Debure, Ludovic;Moreira, Andre;Lewis, Ariane;Huang, Joshua;Thawani, Sujata;Balcer, Laura;Galetta, Steven;Wisniewski, Thomas
通讯作者：
Wisniewski, Thomas
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Alam, Md Masud;Yang, De;Li, Xiao-Qing;Liu, Jia;Back, Timothy Carrel;Trivett, Anna;Karim, Baktiar;Barbut, Denise;Zasloff, Michael;Oppenheim, Joost J.
通讯作者：
Oppenheim, Joost J.