Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China.
Department of Pathology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
J Neuroinflammation. 2020 Sep 17;17(1):272. doi: 10.1186/s12974-020-01940-z.
Microglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. There is significant research on factors that provoke "reactive" or "inflammatory" phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson's disease. On the other hand, it is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e., mostly desirable functions of microglia in a physiological state. What maintains microglia in this physiological state is essentially unknown.
In this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ, IL-4 + IL-13, α-synuclein monomer, and α-synuclein oligomer, and examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP.
We described a novel physiological function of α-synuclein, in which it modulates microglia toward an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways.
These findings suggest a previously unrecognized function of monomeric α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.
小胶质细胞的功能对于维持大脑健康至关重要，其激活是神经退行性变的一个重要组成部分。有大量研究关注在损伤或疾病条件下引发“反应性”或“炎症性”表型的因素。其中一个因素是暴露于聚集或寡聚形式的α-突触核蛋白，一种丰富的大脑蛋白，在驱动小胶质细胞激活中起着至关重要的作用；包括趋化迁移和产生炎症介质在路易体（LB）疾病如帕金森病。另一方面，人们越来越认识到小胶质细胞也会发生变化，这取决于细胞环境，促进主要是重建和抗炎功能，即小胶质细胞在生理状态下的主要理想功能。是什么维持小胶质细胞处于这种生理状态还不清楚。
在这项研究中，我们使用体外和体内模型，用 LPS+IFN-γ、IL-4+IL-13、α-突触核蛋白单体和α-突触核蛋白寡聚体挑战原代小胶质细胞或 BV2 小胶质细胞，通过 RT-PCR、Western blot、ELISA、IF、IHC、Co-IP 检查小胶质细胞表型和潜在机制。
我们描述了α-突触核蛋白的一种新的生理功能，即通过与细胞外信号调节激酶（ERK）相互作用并募集 ERK、核因子 kappa B（NF-κB）和过氧化物酶体增殖物激活受体γ（PPARγ）途径，将小胶质细胞调节为抗炎表型。
这些发现表明单体α-突触核蛋白具有以前未被认识的功能，鉴于其在脑组织中的丰富性和多种功能，这可能为路易体相关疾病及其他疾病的发病机制和潜在治疗提供新的见解。
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