Beckers Lien, Stroobants Stijn, D'Hooge Rudi, Baes Myriam
Laboratory for Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Leuven, Belgium.
Department of Biological Psychology, Faculty of Psychology and Educational Sciences, KU Leuven-University of Leuven, Leuven, Belgium.
Front Cell Neurosci. 2018 May 23;12:136. doi: 10.3389/fncel.2018.00136. eCollection 2018.
It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of neural cells to development of microgliosis and clinical neuropathology, the constitutive mouse model was compared to a neural selective mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive mice, microglia in mice only become mildly inflammatory at end stage of disease. microglia are primed and acquire a chronic and strong inflammatory state in mice whereas microglia in mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in mice and strongly indicates a cell-autonomous role of MFP2 in microglia.
越来越明显的是，小胶质细胞作为中枢神经系统（CNS）的常驻免疫细胞，在神经疾病中起着积极作用。然而，在神经病理状态下，小胶质细胞增生对神经病理学、行为和临床衰退的影响仍不明确。一种缺乏多功能蛋白2（MFP2，过氧化物酶体β氧化中的关键酶）的小鼠模型会发展出一种致命疾病，其特征是出现与人类较轻形式疾病相似的运动问题。人类和小鼠神经衰退的分子机制仍不清楚。该小鼠模型疾病的标志是大脑中小胶质细胞的慢性增殖，而不会引发神经元损失或脱髓鞘。为了确定神经细胞对小胶质细胞增生和临床神经病理学发展的作用，将组成型小鼠模型与神经选择性小鼠模型进行了比较。我们在本研究中证明，与组成型小鼠早期发作且严重的小胶质细胞增生不同，[此处原文似乎有缺失信息]小鼠中的小胶质细胞仅在疾病末期变得轻度炎症。[此处原文似乎有缺失信息]小鼠中的小胶质细胞被激活并呈现慢性且强烈的炎症状态，而[此处原文似乎有缺失信息]小鼠中的小胶质细胞未被激活并处于最小激活状态。与[此处原文似乎有缺失信息]小鼠相比，[此处原文似乎有缺失信息]小鼠中炎症性小胶质细胞表型与更严重的神经元功能障碍、更快的临床恶化和缩短的寿命相关。综上所述，我们的研究表明MFP2的缺失会损害行为和运动能力。[此处原文似乎有缺失信息]小鼠中早期发作且过度的小胶质细胞反应会加剧临床衰退和神经病理学，这强烈表明MFP2在小胶质细胞中具有细胞自主作用。
