Chronic dysregulation of microglial phenotypic balance contributes to prolonged neuroinflammation and neurotoxicity, which is a hallmark of neurodegenerative diseases. Thus, targeting microglial inflammatory signaling represents a promising therapeutic strategy for neurodegenerative diseases. Regulator of G protein Signaling 10 (RGS10) is highly expressed in microglia, where it suppresses pro-inflammatory signaling. However, RGS10 is silenced following microglial activation, augmenting inflammatory responses. While modulating RGS10 expression is a promising strategy to suppress pro-inflammatory microglial activation, no chemical tools with this ability exist. We developed a phenotypic high-throughput assay to screen for compounds with the ability to reverse interferon-γ (IFNγ)-induced RGS10 silencing in BV-2 cells. Identified hits had no effect on RGS10 expression in the absence of stimulus or in response to lipopolysaccharide (LPS). Furthermore, the hits reversed some of the inflammatory gene expression induced by IFNγ. This is the first demonstration of the potential for small molecule intervention to modulate the RGS10 expression in microglia.

中文翻译：

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表型高通量筛选可识别 BV-2 细胞中内源性 RGS10 的小分子调节剂


小胶质细胞表型平衡的慢性失调导致长时间的神经炎症和神经毒性，这是神经退行性疾病的标志。因此，靶向小胶质细胞炎症信号代表了神经退行性疾病的一种有前途的治疗策略。G 蛋白信号转导调节因子 10 （RGS10） 在小胶质细胞中高度表达，可抑制促炎信号转导。然而，RGS10 在小胶质细胞激活后被沉默，从而增强炎症反应。虽然调节 RGS10 表达是抑制促炎性小胶质细胞活化的一种很有前途的策略，但不存在具有这种能力的化学工具。我们开发了一种表型高通量测定法，用于筛选能够在 BV-2 细胞中逆转干扰素γ （IFNγ） 诱导的 RGS10 沉默的化合物。在没有刺激或响应脂多糖 （LPS） 的情况下，鉴定的命中对 RGS10 表达没有影响。此外，命中逆转了 IFNγ 诱导的一些炎症基因表达。这是小分子干预调节小胶质细胞中 RGS10 表达的潜力的首次证明。