Beckers L, Stroobants S, Verheijden S, West B, D'Hooge R, Baes M
KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium.
KU Leuven - University of Leuven, Faculty of Psychology and Educational Sciences, Biological Psychology, B-3000 Leuven, Belgium.
Mol Cell Neurosci. 2017 Apr;80:123-133. doi: 10.1016/j.mcn.2017.03.004. Epub 2017 Mar 7.
An important hallmark of various neurodegenerative disorders is the proliferation and activation of microglial cells, the resident immune cells of the central nervous system (CNS). Mice that lack multifunctional protein-2 (MFP2), the key enzyme in peroxisomal β-oxidation, develop excessive microgliosis that positively correlates with behavioral deficits whereas no neuronal loss occurs. However, the precise contribution of neuroinflammation to the fatal neuropathology of MFP2 deficiency remains largely unknown. Here, we first attempted to suppress the inflammatory response by administering various anti-inflammatory drugs but they failed to reduce microgliosis. Subsequently, Mfp2 mice were treated with the selective colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 as microglial proliferation and survival is dependent on CSF1R signaling. This resulted in the elimination of >95% of microglia from control mice but only 70% of the expanded microglial population from Mfp2 mice. Despite microglial diminution in Mfp2 brain, inflammatory markers remained unaltered and residual microglia persisted in a reactive state. CSF1R inhibition did not prevent neuronal dysfunction, cognitive decline and clinical deterioration of Mfp2 mice. Collectively, the unaltered inflammatory profile despite suppressed microgliosis concurrent with persevering clinical decline strengthens our hypothesis that neuroinflammation importantly contributes to the Mfp2 phenotype.
各种神经退行性疾病的一个重要标志是小胶质细胞（中枢神经系统（CNS）中的常驻免疫细胞）的增殖和激活。缺乏多功能蛋白2（MFP2，过氧化物酶体β氧化中的关键酶）的小鼠会出现过度的小胶质细胞增生，这与行为缺陷呈正相关，而不会发生神经元丢失。然而，神经炎症对MFP2缺乏所致致命神经病理学的确切作用在很大程度上仍不清楚。在这里，我们首先尝试通过给予各种抗炎药物来抑制炎症反应，但它们未能减少小胶质细胞增生。随后，对Mfp2小鼠用选择性集落刺激因子1受体（CSF1R）抑制剂PLX5622进行治疗，因为小胶质细胞的增殖和存活依赖于CSF1R信号传导。这导致对照小鼠中>95%的小胶质细胞被清除，但Mfp2小鼠中仅70%的扩增小胶质细胞群体被清除。尽管Mfp2脑中小胶质细胞减少，但炎症标志物仍未改变，残留的小胶质细胞仍处于反应状态。CSF1R抑制并不能预防Mfp2小鼠的神经元功能障碍、认知下降和临床恶化。总的来说，尽管小胶质细胞增生受到抑制，但炎症特征未改变，同时临床持续衰退，这强化了我们的假设，即神经炎症对Mfp2表型有重要影响。
