WNT signaling in activated microglia is proinflammatory.
WNT signaling in activated microglia is proinflammatory.
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作者：
Halleskog C;Mulder J;Dahlström J;Mackie K;Hortobágyi T;Tanila H;Kumar Puli L;Färber K;Harkany T;Schulte G
小胶质细胞活化是与神经和神经退行性疾病相关的神经炎症的核心，特别是因为活化的小胶质细胞通常是促炎细胞因子的来源。尽管有长达数十年的研究，体内小胶质细胞促炎转化的分子级联仍然很难理解。在这里，我们报告增加β-连环蛋白的表达，WNT信号传导的中央细胞内成分，在小胶质细胞经历一个促炎性形态发生转化与神经炎症相关的致病条件下，如阿尔茨海默氏病。我们证实了疾病相关的β-catenin信号在小胶质细胞在体内显示老年痴呆症样病理（APdE 9）小鼠的年龄依赖性β-catenin积累。在表达WNT受体Frizzled（FZD）4、5、7、8和LDL相关蛋白5/6（LRP 5/6）的培养小鼠小胶质细胞中，我们发现WNT-3A可以稳定β-catenin。WNT-3A剂量依赖性地诱导LRP 6磷酸化，下游激活凌乱的β-连环蛋白稳定和核输入。基因表达谱分析显示，WNT-3A刺激特异性地增加小胶质细胞中促炎免疫反应基因的表达，并加剧从头IL-6、IL-12和肿瘤坏死因子α的释放。总之，我们的数据表明脂糖蛋白的WNT家族可以指导促炎性小胶质细胞转化，并强调β-连环蛋白信号网络在这种细胞类型中的致病意义。
Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly since activated microglia are often a source of pro-inflammatory cytokines. Despite decades-long research, the molecular cascade of pro-inflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased β–catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a pro-inflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation, such as Alzheimer’s disease. We substantiate disease-associated β–catenin signaling in microglia in vivo by showing age-dependent β–catenin accumulation in mice with Alzheimer’s-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled (FZD)4, 5, 7, 8 and LDL related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize β–catenin. WNT-3A dose-dependently induces LRP6 phosphorylation with downstream activation of disheveled, β-catenin stabilization and nuclear import. Gene expression profiling reveals that WNT-3A stimulation specifically increases the expression of pro-inflammatory immune response genes in microglia, and exacerbates the release of de novo IL-6, IL-12 and tumor necrosis factor α. In sum, our data suggest that the WNT family of lipoglycoproteins can instruct pro-inflammatory microglia transformation and emphasize the pathogenic significance of β–catenin signaling networks in this cell type.
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