Peripheral IL-6 from leukocytes controls susceptibility to social defeat stress

描述(申请人提供)：抑郁症和焦虑症等应激障碍与促炎细胞因子白介素6(IL-6)的增加有关，然而，这种升高的来源和功能相关性尚不清楚。利用小鼠重复的社会失败应激模型，我们发现外周免疫反应的个体差异--通过增加白细胞释放IL-6来衡量--预测了应激易感性。易感的小鼠会出现社交回避和快感缺乏，这是啮齿类动物抑郁行为的既定指标。为了了解白细胞来源的IL-6对于社交回避和快感缺乏的发展是否是必要的和充分的，我们用来自压力敏感或IL-6基因敲除(IL-6-/-)小鼠的干细胞产生了骨髓(BM)嵌合体。应激敏感的BM嵌合体表现出基线的快感缺失和增加的应激诱导的社交回避，而IL-6-/-BM嵌合体对应激对这些行为的影响具有抵抗力。此外，我们有初步证据表明，IL-6可能作用于关键的大脑奖赏区域，如伏隔核和前额叶皮质，以调节这些行为效应。我们的工作共同表明，从白细胞释放应激反应IL-6的预先存在的差异在功能上有助于抑郁症样行为表型。在本申请中，我们将定义易感小鼠产生和释放更多IL-6的详细机制。我们将进一步确定这种变化与抑郁症样行为发展的功能相关性，并测试新的治疗策略，如降低应激敏感性的骨髓重组。我们相信，这项工作有望开发基于过度活跃的IL-6反应的预测性诊断测试，以及验证新型抗抑郁药物开发的重要靶点。

DESCRIPTION (provided by applicant): Stress disorders such as depression and anxiety are associated with increases in the pro-inflammatory cytokine interleukin-6 (IL-6), however, the source and functional relevance of this elevation remains unknown. Using a repeated social defeat stress model in mice, we find individual differences in the peripheral immune response to stress-measured by increased IL-6 release from leukocytes-that predicts stress susceptibility. Susceptible mice develop social avoidance and anhedonia, which are established measures of depression-like behavior in rodents. To understand whether leukocyte derived IL-6 is necessary and sufficient for the development of social avoidance and anhedonia, we generated bone marrow (BM) chimeras transplanted with stem cells from stress susceptible or IL-6 knockout (IL-6-/-) mice. Stress susceptible BM chimeras exhibit baseline anhedonia and increased stress-induced social avoidance, whereas IL-6-/- BM chimeras were resistant to the effects of stress on these behaviors. In addition, we have preliminary evidence that IL-6 may be acting within key brain reward regions, such as the nucleus accumbens and prefrontal cortex, to mediate these behavioral effects. Together our work shows that pre-existing differences in stress responsive IL-6 release from leukocytes functionally contributes to depression-like behavioral phenotypes. In this application we will define the detailed mechanisms by which susceptible mice produce and release more IL-6. We will further define the functional relevance of such changes to development of depression-like behavior and test novel therapeutic strategies, such as bone marrow re-engineering to reduce stress susceptibility. We believe that this work holds promise for developing predictive diagnostic tests based on hyperactive IL-6 responses, as well as verification of important targets for novel antidepressant development.