Microglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD. In our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization. We found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α. Our findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.

中文翻译：

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LncRNA HOXA-AS2通过募集PRC2和PGC-1α表达的表观遗传修饰调节小胶质细胞极化

小胶质细胞介导的神经炎症在帕金森病 (PD) 中起重要作用，它根据 M1/M2 极化表型发挥促炎或抗炎作用。因此，促进小胶质细胞向抗炎 M2 表型发展是 PD 的一种潜在治疗方法。长链非编码 RNA (lncRNA) 在神经退行性疾病的进展中至关重要，但人们对它们在 PD 小胶质细胞极化中的作用知之甚少。在我们的研究中，我们使用微阵列分析了 PD 患者外周血单个核细胞 (PBMC) 中 lncRNA 的表达。RT-qPCR 用于在体外和体内评估细胞因子和小胶质细胞标志物的 lncRNA 水平和 mRNA 水平。RIP 和 ChIP 分析分析了 lncRNA 调节小胶质细胞极化的潜在机制。我们发现 HOXA-AS2 在 PD 患者的 PBMC 中上调，并且与过氧化物酶体增殖物激活受体 γ coactivator-1a (PGC-1α) 的表达呈负相关。此外，HOXA-AS2 敲低显着抑制小胶质细胞 M1 极化并通过调节 PGC-1α 表达促进 M2 极化。机制研究表明，HOXA-AS2 可以直接与多梳抑制复合物 2 (PRC2) 相互作用并调节 PGC-1α 启动子的组蛋白甲基化。我们的研究结果确定了上调的 lncRNA HOXA-AS2 通过与 PRC2 复合物相互作用和表观遗传沉默 PGC-1α 来调节小胶质细胞极化来促进神经炎症。HOXA-AS2可能是PD患者小胶质细胞介导的神经炎症的潜在治疗靶点。