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

描述（由申请人提供）：应激障碍（如抑郁和焦虑）与促炎细胞因子白细胞介素-6（IL-6）的升高相关，然而，这种升高的来源和功能相关性仍然未知。在小鼠中使用重复的社会失败压力模型，我们发现外周免疫反应对压力的个体差异-通过增加白细胞释放IL-6来测量-预测压力易感性。易感小鼠会出现社交回避和快感缺乏，这是啮齿动物抑郁样行为的既定指标。为了了解白细胞衍生的IL-6是否是社交回避和快感缺乏的发展所必需和充分的，我们产生了骨髓（BM）嵌合体，其移植有来自应激易感或IL-6敲除（IL-6-/-）小鼠的干细胞。应激敏感的BM嵌合体表现出基线快感缺乏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抗性。此外，我们有初步的证据表明，IL-6可能在关键的大脑奖励区域，如丘脑核和前额叶皮层，介导这些行为效应。我们的工作表明，白细胞释放应激反应性IL-6的预先存在的差异在功能上有助于抑郁样行为表型。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些变化与抑郁样行为发展的功能相关性，并测试新的治疗策略，如骨髓重建以降低应激易感性。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.