Integrin Mac1 mediates paraquat and maneb-induced learning and memory impairments in mice through NADPH oxidase-NLRP3 inflammasome axis-dependent microglial activation.
Integrin Mac1 mediates paraquat and maneb-induced learning and memory impairments in mice through NADPH oxidase-NLRP3 inflammasome axis-dependent microglial activation.
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整合素MAC1通过NADPH氧化酶-NLRP3炎症体依赖轴的小胶质细胞激活，介导百草枯和甘露醇诱导的小鼠学习和记忆损伤。
DOI：
10.1186/s12974-023-02732-x
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发表时间：
2023-02-18
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
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作者：
帕金森病（PD）认知功能障碍的机制尚不清楚。越来越多的证据表明，由小胶质细胞介导的脑神经炎症反应有助于神经病理条件下的认知缺陷，而巨噬细胞抗原复合物-1（Mac 1）是控制小胶质细胞活化的关键因素。采用百草枯和代森锰钠诱导的小鼠PD模型，探讨Mac 1介导的小胶质细胞活化是否参与PD认知功能障碍。使用Morris水迷宫测试测量野生型和Mac 1 −/−小鼠的认知表现。采用免疫组化、Western blot和RT-PCR等方法探讨NADPH氧化酶（NOX）-NLRP 3炎性小体轴在Mac 1介导的小胶质细胞功能障碍、神经元损伤、突触变性和α-synuclein磷酸化（Ser 129）中的作用及机制。Mac 1基因缺失可显著改善百草枯和代森锰引起的小鼠学习记忆障碍、神经元损伤、突触丢失和α-突触核蛋白磷酸化（Ser 129）。随后，发现阻断Mac 1激活可以减轻体内和体外百草枯和代森锰引起的小胶质细胞NLRP 3炎性小体激活。有趣的是，刺激激活的NOX佛波醇肉豆蔻酸酯乙酸酯废除Mac 1阻断肽RGD对百草枯和maneb引起的NLRP 3炎性小体激活的抑制作用，表明NOX在Mac 1介导的NLRP 3炎性小体激活的关键作用。此外，NOX家族的两个成员NOX 1和NOX 2以及下游的PAK 1和MAPK通路被认为是NOX调节NLRP 3炎性小体活化所必需的。最后，NLRP 3炎性体抑制剂格列本脲消除了百草枯和代森锰引起的小胶质细胞M1活化、神经变性和α-突触核蛋白磷酸化（Ser 129），这伴随着小鼠认知能力的改善。Mac 1通过NOX-NLRP 3炎性小体轴依赖性小胶质细胞激活参与小鼠PD模型中的认知功能障碍，为PD认知功能下降提供了新的机制基础。在线版本包含补充材料，可通过10.1186/s12974-023-02732-x获得。
The mechanisms of cognitive impairments in Parkinson’s disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation. To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model. Cognitive performance was measured in wild type and Mac1−/− mice using Morris water maze test. The role and mechanisms of NADPH oxidase (NOX)–NLRP3 inflammasome axis in Mac1-mediated microglial dysfunction, neuronal damage, synaptic degeneration and phosphorylation (Ser129) of α-synuclein were explored by immunohistochemistry, Western blot and RT-PCR. Genetic deletion of Mac1 significantly ameliorated learning and memory impairments, neuronal damage, synaptic loss and α-synuclein phosphorylation (Ser129) caused by paraquat and maneb in mice. Subsequently, blocking Mac1 activation was found to mitigate paraquat and maneb-elicited microglial NLRP3 inflammasome activation in both in vivo and in vitro. Interestingly, stimulating activation of NOX by phorbol myristate acetate abolished the inhibitory effects of Mac1 blocking peptide RGD on paraquat and maneb-provoked NLRP3 inflammasome activation, indicating a key role of NOX in Mac1-mediated NLRP3 inflammasome activation. Furthermore, NOX1 and NOX2, two members of NOX family, and downstream PAK1 and MAPK pathways were recognized to be essential for NOX to regulate NLRP3 inflammasome activation. Finally, a NLRP3 inflammasome inhibitor glybenclamide abrogated microglial M1 activation, neurodegeneration and phosphorylation (Ser129) of α-synuclein elicited by paraquat and maneb, which were accompanied by improved cognitive capacity in mice. Mac1 was involved in cognitive dysfunction in a mouse PD model through NOX–NLRP3 inflammasome axis-dependent microglial activation, providing a novel mechanistic basis of cognitive decline in PD. The online version contains supplementary material available at 10.1186/s12974-023-02732-x.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
7.1
作者：
Arawaka S;Sato H;Sasaki A;Koyama S;Kato T
通讯作者：
Kato T
影响因子：
3.7
作者：
Codolo G;Plotegher N;Pozzobon T;Brucale M;Tessari I;Bubacco L;de Bernard M
通讯作者：
de Bernard M
DOI：
10.3390/antiox11061202
发表时间：
2022-06-20
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
9
作者：
Che Y;Hou L;Sun F;Zhang C;Liu X;Piao F;Zhang D;Li H;Wang Q
通讯作者：
Wang Q