iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson's Disease.
iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson's Disease.
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DOI：
10.3389/fcell.2021.740758
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发表时间：
2021
影响因子：
5.5
通讯作者：
Grünewald A
中科院分区：
文献类型：
--
作者：
Badanjak K;Mulica P;Smajic S;Delcambre S;Tranchevent LC;Diederich N;Rauen T;Schwamborn JC;Glaab E;Cowley SA;Antony PMA;Pereira SL;Venegas C;Grünewald A
帕金森病（PD）是一种神经退行性疾病，大多数患者的病因不明，因此被认为是“特发性”（IPD）。PD主要影响黑质丘脑部（SNpc）中的多巴胺能神经元，但病理学并不限于这种细胞类型。年龄的增长被认为是IPD发展的主要危险因素，并极大地影响了小胶质细胞（大脑的免疫细胞）的功能。随着年龄的增长，小胶质细胞变得功能障碍，并释放促炎因子到细胞外空间，这促进神经元细胞死亡。因此，神经炎症也被描述为PD的特征。到目前为止，探索IPD患者样本中炎症途径的研究主要集中在血液来源的免疫细胞或脑切片上，但很少在体外研究患者的小胶质细胞。因此，我们决定使用iPSC衍生的培养物和死后组织以比较的方式探索小胶质细胞对IPD的贡献。我们对已发表的RNAseq数据集的荟萃分析表明，IPD患者的黑质组织中IL 10和IL 1B上调。我们观察到这些细胞因子在小胶质细胞的表达水平增加相比，神经元使用我们的单细胞中脑图谱。此外，与对照小胶质细胞相比，IPD中IL 10和IL 1B上调。接下来，为了在体外验证这些发现，我们使用已建立的分化方案从iPSC产生IPD患者小胶质细胞。LPS处理后，IPD小胶质细胞更容易引发，如IL 1B和IL 10基因表达升高以及NLRP 3的mRNA和蛋白水平升高所示。此外，IPD小胶质细胞在基础条件下具有更高的吞噬能力，这种表型在LPS刺激后进一步加剧，表明小胶质细胞功能异常。我们的研究结果表明，小胶质细胞的重要性，在IPD的神经炎症过程中的关键球员。虽然我们的研究强调了小胶质细胞介导的炎症信号在IPD中的重要性，但还需要进一步的研究来探索这些细胞中的特定疾病机制。
Parkinson’s disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered “idiopathic” (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions—a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.
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影响因子：
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作者：
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通讯作者：
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通讯作者：
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