HuR promotes the molecular signature and phenotype of activated microglia: Implications for amyotrophic lateral sclerosis and other neurodegenerative diseases.
HuR promotes the molecular signature and phenotype of activated microglia: Implications for amyotrophic lateral sclerosis and other neurodegenerative diseases.
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作者：
Matsye P;Zheng L;Si Y;Kim S;Luo W;Crossman DK;Bratcher PE;King PH
在神经退行性疾病如肌萎缩性侧索硬化症（ALS）中，小胶质细胞的慢性激活有助于疾病进展。激活的小胶质细胞产生细胞因子、趋化因子和其他因子，这些因子通常直接或通过募集其他免疫细胞来清除感染或受损组织。驱动这种表型的分子程序通常与转录因子NF-κB相关，并以IL-1β、TNF-α和IL-6等促炎因子的上调为特征。在这里，我们研究了HuR（一种通过转录后途径调节基因表达的RNA结合蛋白）在活化小胶质细胞的分子和细胞表型中的作用。我们对hr沉默的小胶质细胞进行了RNA测序，发现脂多糖诱导的IL-1β和TNF-α炎症途径以及其他促进小胶质细胞迁移和侵袭的因素显著减弱。RNA动力学和荧光素酶报告研究表明，这种衰减与启动子活性的改变有关，而不是与RNA稳定性的变化有关。hr沉默的小胶质细胞表现出迁移、侵袭和趋化特性的减少，但保持了活力。MMP-12是一个对HuR敲低非常敏感的靶标，参与迁移/入侵表型。在肌萎缩侧索硬化症脊髓活化小胶质细胞的细胞质室中大量检测到HuR，与其活性增加一致。来自als相关突变SOD1小鼠的小胶质细胞表现出更高的迁移/侵袭特性，可以通过HuR抑制来阻止。这些发现强调了HuR在塑造活化小胶质细胞的分子特征和表型方面的重要作用，并可能成为ALS和其他神经退行性疾病的治疗靶点。
In neurodegenerative disease like amyotrophic lateral sclerosis (ALS), chronic activation of microglia contributes to disease progression. Activated microglia produce cytokines, chemokines and other factors that normally serve to clear infection or damaged tissue either directly or through the recruitment of other immune cells. The molecular program driving this phenotype is classically linked to the transcription factor NF-κB and characterized by the upregulation of pro-inflammatory factors such as IL-1β, TNF-α, and IL-6. Here, we investigated the role of HuR, an RNA binding protein that regulates gene expression through posttranscriptional pathways, on the molecular and cellular phenotypes of activated microglia. We performed RNA sequencing of HuR-silenced microglia and found significant attenuation of lipopolysaccharide-induced IL-1β and TNF-α inflammatory pathways and other factors that promote microglial migration and invasion. RNA kinetics and luciferase reporter studies suggested that the attenuation was related to altered promoter activity rather than a change in RNA stability. HuR-silenced microglia showed reduced migration, invasion and chemotactic properties but maintained viability. MMP-12, a target exquisitely sensitive to HuR knockdown, participates in the migration/invasion phenotype. HuR is abundantly detected in the cytoplasmic compartment of activated microglia from ALS spinal cords consistent with its increased activity. Microglia from ALS-associated mutant SOD1 mice demonstrated higher migration/invasion properties which can be blocked with HuR inhibition. These findings underscore an important role for HuR in sculpting the molecular signature and phenotype of activated microglia, and as a possible therapeutic target in ALS and other neurodegenerative diseases.
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Cherry JD;Olschowka JA;O'Banion MK
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