Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal β-oxidation deficiency.
Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal β-oxidation deficiency.
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作者：
Verheijden S;Beckers L;Casazza A;Butovsky O;Mazzone M;Baes M
慢性炎症的中枢神经系统(CNS)中反应性小胶质细胞的功能多样性和分子适应性还知之甚少。我们之前的研究表明，缺乏多功能蛋白2的小鼠在中枢神经系统灰质中持续积聚反应性髓系细胞。多功能蛋白2是过氧化体β氧化的关键酶。在这里，我们表明髓系细胞数量的增加完全来自驻留的小胶质细胞的增殖，而不是浸润性的单核细胞。急性分离后通过基因表达谱确定Mfp2−/−小胶质细胞的特征，并通过定量聚合酶链式反应、免疫组织化学和流式细胞仪分析进行验证。比较肌萎缩侧索硬化症模型SOD1G93A小鼠和Mfp2−/−小胶质细胞的特点。与SOD1G93A脊髓的神经退变环境相反，Mfp2−/−脑内神经元完整，Mfp2−/−小胶质细胞缺乏吞噬和神经毒性活性的迹象。伴随着Mfp2−/−小胶质细胞的慢性反应状态的是，在稳态条件下，指定独特的小胶质细胞特征的标志物下调。相反，哺乳动物的雷帕霉素靶标(MTOR)以及下游的糖酵解和蛋白质翻译途径被诱导，这表明代谢适应。Mfp2−/−小胶质细胞被免疫激活，但并未分化为促炎或抗炎表型。外周内毒素刺激在Mfp2−/−脑内引发了夸大的炎症反应，这与启动状态一致。综上所述，我们证明驻留的小胶质细胞的慢性激活并不一定会导致吞噬作用或明显的神经毒性。
The functional diversity and molecular adaptations of reactive microglia in the chronically inflamed central nervous system (CNS) are poorly understood. We previously showed that mice lacking multifunctional protein 2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, persistently accumulate reactive myeloid cells in the gray matter of the CNS. Here we show that the increased numbers of myeloid cells solely derive from proliferation of resident microglia and not from infiltrating monocytes. We defined the signature of Mfp2−/− microglia by gene expression profiling after acute isolation, which was validated by quantitative PCR, immunohistochemical and flow cytometric analysis. The features of Mfp2−/− microglia were compared with those from SOD1G93A mice, an amyotrophic lateral sclerosis model. In contrast to the neurodegenerative milieu of SOD1G93A spinal cord, neurons were intact in Mfp2−/− brain and Mfp2−/− microglia lacked signs of phagocytic and neurotoxic activity. The chronically reactive state of Mfp2−/− microglia was accompanied by downregulation of markers that specify the unique microglial signature in homeostatic conditions. In contrast, mammalian target of rapamycin (mTOR) and downstream glycolytic and protein translation pathways were induced, indicative of metabolic adaptations. Mfp2−/− microglia were immunologically activated but not polarized to a pro- or anti-inflammatory phenotype. A peripheral lipopolysaccharide challenge provoked an exaggerated inflammatory response in Mfp2−/− brain, consistent with a primed state. Taken together, we demonstrate that chronic activation of resident microglia does not necessarily lead to phagocytosis nor overt neurotoxicity.
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