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IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

View ORCID ProfileJinqiang Zhang, View ORCID ProfilePeijing Rong, Lijuan Zhang, Hui He, Tao Zhou, Yonghua Fan, Li Mo, View ORCID ProfileQiuying Zhao, Yue Han, Shaoyuan Li, Yifei Wang, Wan Yan, View ORCID ProfileHuafu Chen, View ORCID ProfileZili You
doi: https://doi.org/10.1101/2020.02.01.929646
Jinqiang Zhang
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, ChinaGuizhou University of Traditional Chinese Medicine, Guiyang 550025, China
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  • ORCID record for Jinqiang Zhang
Peijing Rong
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
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Lijuan Zhang
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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Hui He
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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Tao Zhou
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
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Yonghua Fan
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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Li Mo
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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Qiuying Zhao
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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Yue Han
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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Shaoyuan Li
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
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Yifei Wang
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
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Wan Yan
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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Huafu Chen
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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  • For correspondence: youzili@uestc.edu.cn chenhf@uestc.edu.cn
Zili You
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, China
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  • For correspondence: youzili@uestc.edu.cn chenhf@uestc.edu.cn
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Abstract

Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific groups of microglia and is functionally implicated in behavioral responses to stress. However, the role of microglia in modulating hippocampal neurogenesis in stress responses remains poorly understood. Here we investigated the effects of IL4-driven Arg1+ microglia in the restoration of hippocampal neurogenesis and conferment of stress resilience. We found that low IL4 levels in the hippocampus of mice was associated with greater stress vulnerability and, conversely, overexpression of IL4 in the hippocampus induced a large number of Arg1+ microglia and ameliorated stress-induced depressive-like behaviors. Knockdown of microglial IL4 receptors in the hippocampus of mice exacerbated the stress-induced inflammatory response and abolished the antidepressant effects of IL4 overexpression. Enhancement or inhibition of IL4 signaling in hippocampal microglia modulated neurogenesis, and blockade of neurogenesis abolished the resilience to stress-induced depression. We further show that IL4-activated microglia is associated with upregulation of BDNF levels and neurogenesis. Taken together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis in response to chronic stress, helping protect against depressive-like symptoms. These findings identify the modulation of a specific microglial phenotype as a treatment strategy for mood disorders.

In Brief Zhang et al. show that IL4-induced Arg1+ microglia restore hippocampal neurogenesis and promote resilience against stress in mice by increasing BDNF levels. Targeting microglia with immunomodulatory factors may be a strategy for treating mood disorders.

Highlights

  1. Vulnerability to stress in mice is associated with reduced IL4 signaling in the hippocampus

  2. Brain-derived IL4 promotes adult hippocampal neurogenesis and stress resistance by driving Arg1+ microglia

  3. IL4-driven Arg1+ microglia enhance hippocampal neurogenesis via a BDNF-dependent pathway

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 02, 2020.
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IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis
Jinqiang Zhang, Peijing Rong, Lijuan Zhang, Hui He, Tao Zhou, Yonghua Fan, Li Mo, Qiuying Zhao, Yue Han, Shaoyuan Li, Yifei Wang, Wan Yan, Huafu Chen, Zili You
bioRxiv 2020.02.01.929646; doi: https://doi.org/10.1101/2020.02.01.929646
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IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis
Jinqiang Zhang, Peijing Rong, Lijuan Zhang, Hui He, Tao Zhou, Yonghua Fan, Li Mo, Qiuying Zhao, Yue Han, Shaoyuan Li, Yifei Wang, Wan Yan, Huafu Chen, Zili You
bioRxiv 2020.02.01.929646; doi: https://doi.org/10.1101/2020.02.01.929646

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