Interleukin-4 Protects Dopaminergic Neurons In vitro but Is Dispensable for MPTP-Induced Neurodegeneration In vivo.
Interleukin-4 Protects Dopaminergic Neurons In vitro but Is Dispensable for MPTP-Induced Neurodegeneration In vivo.
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DOI：
10.3389/fnmol.2017.00062
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发表时间：
2017
影响因子：
4.8
通讯作者：
Spittau B
中科院分区：
文献类型：
--
作者：
Hühner L;Rilka J;Gilsbach R;Zhou X;Machado V;Spittau B
小胶质细胞参与中枢神经系统(CNS)的生理和神经病理过程。它们的功能状态通常被称为M1样激活和M2样激活，被认为分别参与了神经炎症介导的神经变性或神经保护。帕金森病是最常见的神经退行性疾病之一，其特征是黑质中脑多巴胺能神经元进行性丢失，导致运动迟缓、震颤和强直。白介素4(IL4)介导的小胶质细胞M2样活化，其特征是交替标记精氨酸酶1(Arg1)和类几丁质酶3(YM1)，已在体外得到了很好的研究，但内源性IL4在体内中枢神经系统病理过程中的作用尚不清楚。有趣的是，IL4激活的小胶质细胞被描述为促进神经保护和神经恢复作用，这可能是减缓神经退行性疾病进展的重要因素。在本研究中，我们探讨了内源性和外源性IL4在体外MPP+诱导的丙二醛神经元变性中的作用，并进一步探讨了IL4缺乏对1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)小鼠帕金森病模型体内神经元变性的影响。我们的结果清楚地表明，外源性IL4对体外培养的MDA神经元具有重要的保护作用，但内源性IL4对黑质纹状体系统的发育和维持以及MPTP诱导的体内TH+神经元的丢失似乎是必不可少的。这些结果强调了IL4在促进神经保护性小胶质细胞激活状态中的重要性，并加强了外源性IL4对PD模型中MDA神经元的保护作用。
Microglia are involved in physiological as well as neuropathological processes in the central nervous system (CNS). Their functional states are often referred to as M1-like and M2-like activation, and are believed to contribute to neuroinflammation-mediated neurodegeneration or neuroprotection, respectively. Parkinson’s disease (PD) is one the most common neurodegenerative disease and is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra resulting in bradykinesia, tremor, and rigidity. Interleukin 4 (IL4)-mediated M2-like activation of microglia, which is characterized by upregulation of alternative markers Arginase 1 (Arg1) and Chitinase 3 like 3 (Ym1) has been well studied in vitro but the role of endogenous IL4 during CNS pathologies in vivo is not well understood. Interestingly, microglia activation by IL4 has been described to promote neuroprotective and neurorestorative effects, which might be important to slow the progression of neurodegenerative diseases. In the present study, we addressed the role of endogenous and exogenous IL4 during MPP+-induced degeneration of mDA neurons in vitro and further addressed the impact of IL4-deficiency on neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Our results clearly demonstrate that exogenous IL4 is important to protect mDA neurons in vitro, but endogenous IL4 seems to be dispensable for development and maintenance of the nigrostriatal system as well as MPTP-induced loss of TH+ neurons in vivo. These results underline the importance of IL4 in promoting a neuroprotective microglia activation state and strengthen the therapeutic potential of exogenous IL4 for protection of mDA neurons in PD models.