Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety.
Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety.
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DOI：
10.1038/mp.2017.64
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发表时间：
2018-06
影响因子：
11
通讯作者：
Godbout JP
中科院分区：
文献类型：
--
作者：
McKim DB;Weber MD;Niraula A;Sawicki CM;Liu X;Jarrett BL;Ramirez-Chan K;Wang Y;Roeth RM;Sucaldito AD;Sobol CG;Quan N;Sheridan JF;Godbout JP
社会心理压力会导致焦虑和抑郁的发生。最近的临床研究报告称，患有压力相关精神疾病的个体循环中炎症性白细胞增加。与此同时，我们对小鼠的研究表明，社会压力会导致炎症单核细胞释放到循环中。此外，社会压力会导致长期焦虑的发展，而这种焦虑依赖于大脑中的炎症单核细胞。因此，我们假设慢性压力会促进炎症单核细胞的产生，这些单核细胞被小胶质细胞积极招募到大脑，而这些单核细胞会增强神经炎症信号并延长焦虑。在这里，我们表明，小鼠反复的社交失败压力激活了大脑中的威胁评估中心，该中心在空间上与小胶质细胞激活和单核细胞募集的内皮促进一致。此外，在应激前用 CSF1R 拮抗剂清除小胶质细胞可以阻止单核细胞向大脑的募集，并消除焦虑的发展。细胞特异性转录分析显示，小胶质细胞选择性增强 CCL2 表达，而单核细胞表达促炎细胞因子 IL-1β。与这些情况一致，招募的具有应激的炎症单核细胞粘附于 IL-1R1+ 神经血管内皮细胞，并且这种相互作用被小胶质细胞耗竭所阻断。此外，在骨髓源性细胞中，caspase-1KO 特异性地破坏 IL-1β 信号传导，结果表明单核细胞通过 IL-1β 刺激神经血管 IL-1R1 来促进焦虑的发生。总的来说，压力期间焦虑的发展是由小胶质细胞募集产生 IL-1β 的单核细胞刺激脑内皮 IL-1R1 引起的。因此，单核细胞 IL-1β 的产生代表了一种新的机制，它是与压力相关的精神疾病相关的行为并发症的基础。
Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine IL-1β. Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1+ neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1β signaling by caspase-1KO specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1β. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes that stimulated brain endothelial IL-1R1. Thus, monocyte IL-1β production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.
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DOI：
10.1073/pnas.1205858109
发表时间：
2012-09-11
影响因子：
11.1
作者：
Capotondo, Alessia;Milazzo, Rita;Biffi, Alessandra
通讯作者：
Biffi, Alessandra
DOI：
10.1016/j.bbi.2014.02.006
发表时间：
2014-08
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Quan N
通讯作者：
Quan N
影响因子：
--
作者：
Kendler, KS;Hettema, JM;Prescott, CA
通讯作者：
Prescott, CA
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.3
作者：
Liu, Xiaoyu;Yamashita, Tetsuji;Quan, Ning
通讯作者：
Quan, Ning