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首页> 外文期刊>Journal of cellular physiology. >LRRK2 and WAVE2 regulate microglial-transition through distinct morphological phenotypes to induce neurotoxicity in a novel two-hit in vitro model of neurodegeneration
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LRRK2 and WAVE2 regulate microglial-transition through distinct morphological phenotypes to induce neurotoxicity in a novel two-hit in vitro model of neurodegeneration

机译：LRRK2和WAVE2 microglial-transition进行监管通过不同的形态学表型小说两面夹攻体外诱导神经毒性神经退化模型

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摘要

We report a novel in vitro classification system that tracks microglial activation state and their potential neurotoxicity. Mixed live-cell imaging was used to characterize transition through distinct morphological phenotypes, production of reactive oxygen species (ROS), formation of reactive microglial aggregates, and subsequent cytokine production. Trans-well cultures were used to determine microglial migration (control and lipopolysaccharide (LPS) treated) to glutamate pre-stressed or healthy neurons. This two-hit paradigm was developed to model the vast evidence that neurodegenerative conditions, like Parkinson's disease (PD), may stem from the collective impact of multiple environmental stressors. We found that healthy neurons were resistant to microglial-mediated inflammation, whereas glutamate pre-stressed neurons were highly susceptible and in fact, appeared to recruit microglia. The LPS treated microglia progressed through distinct morphological states and expressed high levels of ROS and formed large cellular aggregates. Recent evidence implicates leucine-rich repeat kinase 2 (LRRK2) as an important player in the microglial inflammatory state, as well as in the genesis of PD. We found that inhibition of the LRRK2 signaling pathway using the kinase inhibitor cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi2) or inhibition of the actin regulatory protein, Wiskott-Aldrich syndrome family Verprolin-homologous Protein-2 (WAVE2), stunted microglial activation and prevented neurotoxicity. Furthermore, inhibition of LRRK2 kinase activity reduced pro-inflammatory chemokines including MIP-2, CRG-2, and RANTES. These data together support the notion that LRRK2 and WAVE2 are important mediators of cytokine production and cytoskeletal rearrangement necessary for microglial-induced neurotoxicity. Furthermore, our model demonstrated unique microglial phenotypic changes that might be mechanistically important for better understanding neuron-microglial crosstalk.
机译：我们报告一个小说体外分类系统跟踪和小胶质激活状态潜在的神经毒性。被用来描述过渡不同的形态表型,生产的活性氧(ROS)的形成反应性小胶质总量,和后续细胞因子的生产。用于确定小胶质迁移(控制和脂多糖(LPS))来治疗谷氨酸预应力或健康的神经元。两面夹攻范式是广阔的开发模型证据表明,神经退行性条件,帕金森病(PD),可能源于集体多个环境的影响紧张的因素。耐microglial-mediated炎症,而谷氨酸预应力神经元高度敏感,事实上,似乎招募小胶质细胞。通过不同形态的国家发展和表达高水平的ROS,形成大细胞聚集。体内基因LRRK2富亮氨酸重复激酶2()作为一个重要的球员在小胶质炎症状态,以及在PD的起源。体内基因LRRK2的抑制信号通路使用激酶抑制剂

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