Type 1 Interleukin-4 Signaling Obliterates Mouse Astroglia in vivo but Not in vitro
Type 1 Interleukin-4 Signaling Obliterates Mouse Astroglia in vivo but Not in vitro
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DOI：
10.3389/fcell.2020.00114
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发表时间：
2020-02-26
影响因子：
5.5
通讯作者：
Kizil, Caghan
中科院分区：
文献类型：
--
作者：
Mashkaryan, Violeta;Siddiqui, Tohid;Kizil, Caghan
最近的研究结果表明，神经发生减少可能是人类神经病理恶化的潜在原因之一，因此恢复神经干细胞增殖和神经发生有助于规避阿尔茨海默病的一些病理方面。我们最近发现，白细胞介素-4/STAT6信号是一种神经元-胶质细胞串音机制，可促进成年斑马鱼大脑和人类星形胶质细胞3D培养物中的胶质细胞增殖和神经发生，具有神经发生特性。本研究通过APP/PS1dE9 AD小鼠模型的单细胞测序，我们发现il - 4受体（Il4r）在小鼠星形胶质细胞中不表达，il - 4信号在这些细胞中不活跃。我们测试了激活IL4/STAT6信号是否会增强健康和疾病条件下的细胞增殖和神经发生。慢病毒介导的IL4R或组成型活性STAT6VT的表达在体内损害了小鼠星形胶质细胞的存活能力，但在体外没有损害。这些结果表明，与斑马鱼大脑和体外哺乳动物细胞培养相比，成年小鼠大脑产生了一个不允许的环境，指示了il - 4信号对星形胶质细胞存活和神经发生特性的负面影响。我们的研究发现，成年小鼠脑齿状回（DG）中的IL4R信号影响DG细胞的存活，这暗示了一种可能导致大脑神经再生能力丧失的进化机制，这可能用于神经退行性疾病的基础和临床方面。
Recent findings suggest that reduced neurogenesis could be one of the underlying reasons for the exacerbated neuropathology in humans, thus restoring the neural stem cell proliferation and neurogenesis could help to circumvent some pathological aspects of Alzheimer's disease. We recently identified Interleukin-4/STAT6 signaling as a neuron-glia crosstalk mechanism that enables glial proliferation and neurogenesis in adult zebrafish brain and 3D cultures of human astroglia, which manifest neurogenic properties. In this study, by using single cell sequencing in the APP/PS1dE9 mouse model of AD, we found that IL4 receptor (Il4r) is not expressed in mouse astroglia and IL4 signaling is not active in these cells. We tested whether activating IL4/STAT6 signaling would enhance cell proliferation and neurogenesis in healthy and disease conditions. Lentivirus-mediated expression of IL4R or constitutively active STAT6VT impaired the survival capacity of mouse astroglia in vivo but not in vitro. These results suggest that the adult mouse brain generates a non-permissive environment that dictates a negative effect of IL4 signaling on astroglial survival and neurogenic properties in contrast to zebrafish brains and in vitro mammalian cell cultures. Our findings that IL4R signaling in dentate gyrus (DG) of adult mouse brain impinges on the survival of DG cells implicate an evolutionary mechanism that might underlie the loss of neuroregenerative ability of the brain, which might be utilized for basic and clinical aspects for neurodegenerative diseases.