Alterations of the Innate Immune System in Susceptibility and Resilience After Social Defeat Stress.
Alterations of the Innate Immune System in Susceptibility and Resilience After Social Defeat Stress.
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DOI：
10.3389/fnbeh.2018.00141
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发表时间：
2018
影响因子：
3
通讯作者：
Alferink J
中科院分区：
文献类型：
--
作者：
Ambrée O;Ruland C;Scheu S;Arolt V;Alferink J
先天免疫反应失调在压力相关的精神疾病如重度抑郁症中经常被报道。在小鼠中，发现应激暴露后循环细胞因子水平增强以及先天免疫细胞数量改变。此外，应激诱导的外周单核细胞向大脑的募集已被证明会促进焦虑样行为。然而，目前尚不清楚先天免疫系统的特异性差异是否与小鼠的应激易感性或恢复力有关。利用慢性社会失败，抑郁和压力脆弱性模型，我们表征了应激易感和弹性动物的外周和脑入侵髓细胞。在所有失败的动物中，我们通过流式细胞术发现，与未失败的对照组相比，脾脏中CD11c+树突状细胞（dc）的百分比降低。仅在易感小鼠中，传统的脾脏dc显示MHC II类和共刺激CD80分子的上调表达，这表明这些细胞的成熟表型增强。易感而非弹性的动物进一步表现出炎症性Ly6Chi单核细胞增加和脾脏来源的CD11b+细胞数量增加，这些细胞在脂多糖（LPS）刺激下产生促炎细胞因子肿瘤坏死因子（TNF）。外周CD45hi - CD11b+细胞迁移到失败小鼠大脑的百分比增加，无论恢复能力或易感性如何。然而，易感小鼠大脑中的细胞浸润含有较高百分比的CC趋化因子受体2 (CCR2+) Ly6Chi单核细胞，代表炎症表型。因此，我们在易感和弹性小鼠中定义了涉及常规dc和炎性Ly6Chi单核细胞的特异性应激相关免疫特征。总之，我们的研究结果表明，先天免疫系统对压力相关疾病（如重度抑郁症）的易感性有影响。
Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c+ dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6Chi monocytes and higher numbers of spleen-derived CD11b+ cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45hi CD11b+ cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2+) Ly6Chi monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6Chi monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.
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