Wies Mancini Victoria Sofia Berenice, Di Pietro Anabella Ayelen, Pasquini Laura Andrea
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica, Cátedra de Química Biológica Patológica; Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
Neural Regen Res. 2023 Feb;18(2):267-272. doi: 10.4103/1673-5374.346538.
Multiple sclerosis is a chronic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation, genetic predisposition, and environmental factors. The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology, playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration. Even though reactive microglia can damage tissue and heighten deleterious effects and neurodegeneration, activated microglia also perform neuroprotective functions such as debris phagocytosis and growth factor secretion. Astrocytes can be activated into pro-inflammatory phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia, which could also mediate neurodegeneration. This A1 phenotype inhibits oligodendrocyte proliferation and differentiation and is toxic to both oligodendrocytes and neurons. However, astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism. A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation, progression, and resolution of the disease. The colony-stimulating factor-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia. Importantly, as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling, colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain. In this context, the present review discusses the impact of microglial depletion through colony-stimulating factor-1 receptor inhibition on demyelination, neurodegeneration, astroglial activation, and behavior in different multiple sclerosis models, highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.
多发性硬化症是一种慢性中枢神经系统脱髓鞘疾病，其发病和进展由免疫失调、遗传易感性和环境因素共同驱动。小胶质细胞和星形胶质细胞的激活是多发性硬化症免疫病理学中的关键因素，在疾病的解剖位置和阶段发挥特定作用，并控制脱髓鞘和神经退行性变。尽管反应性小胶质细胞会损害组织并加剧有害影响和神经退行性变，但激活的小胶质细胞也具有神经保护功能，如碎片吞噬和生长因子分泌。星形胶质细胞可通过活化的神经炎性小胶质细胞介导的机制被激活为促炎表型A1，这也可能介导神经退行性变。这种A1表型抑制少突胶质细胞的增殖和分化，对少突胶质细胞和神经元均有毒性。然而，星形胶质细胞也可能因神经退行性变而被激活为A2表型，作为一种保护机制。多种模拟特定多发性硬化症特征及相关病理生理过程的动物模型，有助于确定导致疾病起始、进展和缓解的一系列事件。集落刺激因子-1受体由外周单核细胞、巨噬细胞和中枢神经系统小胶质细胞等髓系细胞表达。重要的是，由于小胶质细胞的发育和存活严重依赖集落刺激因子-1受体信号传导，抑制集落刺激因子-1受体几乎可以完全清除大脑中的小胶质细胞。在此背景下，本综述讨论了通过抑制集落刺激因子-1受体使小胶质细胞耗竭对不同多发性硬化症模型中的脱髓鞘、神经退行性变、星形胶质细胞激活和行为的影响，强调了小胶质细胞对脱髓鞘疾病进展影响的多样性以及在治疗设计中调节小胶质细胞的优缺点。
