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

来自白细胞的外周 IL-6 控制对社交失败压力的易感性

基本信息

批准号：
9275540
负责人：
MIRIAM MERAD
金额：
$ 59.69万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-24 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275540
关键词：
Anhedonia Animals Antidepressive Agents Anxiety Astrocytes Attention Behavior Behavioral Biological Markers Bone Marrow Bone Marrow Stem Cell Bone Marrow Transplantation Brain Cell Compartmentation Cell Count Cells Cellular Stress Chimera organism Data Development Diagnostic tests Engineering Epigenetic Process Exhibits Family Genetic Goals Grant Hematopoietic stem cells Hour Hyperactive behavior Immune Immune Cell Activation Immune response Immune system Inbred Strains Mice Individual Differences Inflammatory Inflammatory Response Injectable Interleukin-6 Knock-out Knockout Mice Leukocytes Lipopolysaccharides Measures Mediating Mental Depression Messenger RNA MicroRNAs Microglia Modeling Molecular Profiling Mus Neuraxis Nucleus Accumbens Organ Peripheral Phenotype Play Predisposition Prefrontal Cortex Regulation Resistance Rewards Rodent Role Social Development Social Interaction Source Stem cells Stress Stromal Cells Testing Transplantation Work anxiety-like behavior base behavior test behavioral response biological adaptation to stress cell type cytokine depression model irradiation neutralizing antibody novel novel therapeutics overexpression public health relevance reconstitution resilience response small hairpin RNA social stress disorder

项目摘要

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.

描述（由申请人提供）：抑郁症和焦虑等应激障碍与促炎性细胞因子白介素-6（IL-6）的增加有关，但是，该高程的来源和功能相关性仍然未知。使用小鼠中反复的社会失败压力模型，我们发现在白细胞中IL-6释放增加的IL-6释放的外周免疫反应中的个体差异 - 预测应力敏感性。易感小鼠发展了社会回避和Anhedonia，这是啮齿动物中类似抑郁症行为的措施。为了了解白细胞衍生的IL-6是否必要且足以发展社会回避和Anhedonia，我们产生了骨髓（BM）嵌合体，该嵌合体从易感性易感性或IL-6敲除（IL-6 - / - ）小鼠中移植的干细胞移植。。压力易感的BM嵌合体表现出基线抗逆性和压力引起的社会回避，而IL-6 - / - BM嵌合体对压力对这些行为的影响有抵抗力。此外，我们有初步证据表明IL-6可能在关键的大脑奖励区域（例如伏隔核和前额叶皮层）作用以介导这些行为效应。我们的工作共同表明，从白细胞释放的应力响应IL-6在功能上释放的差异在功能上有助于抑郁样的行为表型。在此应用中，我们将定义易感小鼠产生并释放更多IL-6的详细机制。我们将进一步定义此类变化与抑郁症行为发展和测试新型治疗策略的功能相关性，例如骨髓重新设计以降低压力敏感性。我们认为，这项工作具有基于多动IL-6反应以及对新型抗抑郁药发育的重要目标的验证，开发预测性诊断测试的希望。