Role of Commensal Microbiota in Stressor-Induced Immunomodulation

描述（由申请人提供）：慢性炎症性疾病每年影响数百万美国人，并对患者和社会产生重大的医疗、心理社会和经济影响。多发性硬化症是一种慢性退行性神经系统疾病，涉及免疫介导的炎症性脱髓鞘过程，并可因合并症（如压力和焦虑）而显著加重。尽管有了这些知识，但这种情况发生的机制还没有得到很好的理解。本研究将测试一个高度新颖的综合假设，即肠道微生物群参与应激源诱导的全身性炎症的增强，从而导致多发性硬化症动物模型的症状恶化。我们已经取得了令人兴奋的发现，肠道微生物群对于应激源诱导的脾IL-1 -¿的增加是必要的。这很重要，因为IL-1在包括多发性硬化症在内的许多慢性炎症性疾病的发展中起着核心作用。在应激源暴露期间，微生物群如何导致IL-1增加，以及对慢性炎症疾病的影响，目前尚不清楚。在反复的社会失败中，共生微生物可以从它们的主要生态位转移到身体内部。由于越来越多的证据表明神经内分泌激素，如交感神经系统衍生的儿茶酚胺激素，可以影响微生物种群，Aim 1将测试应激源诱导的交感神经系统激活是否会导致共生微生物群的易位。为了进一步证实微生物易位对于应激源诱导的免疫增强是必要的，Aim 2将验证应激源诱导的脾脏IL-1 -¿增加依赖于巨噬细胞模式识别受体信号传导和炎性体形成的假设。最后，为了确定微生物群是否与应激源诱导的慢性疾病恶化有关，我们将采用一种广泛使用的多发性硬化症动物模型，即实验性自身免疫性脑脊髓炎（EAE）。反复社交失败对EAE进展的影响将在无菌小鼠（即从未接触过共生微生物的小鼠）和常规小鼠中确定。通过整合目标1、2和3的结果，我们将确定应激源暴露可以加剧慢性炎症性疾病的新机制。这些发现将最终促进合理设计和使用针对微生物群的治疗方法来治疗慢性疾病。

DESCRIPTION (provided by applicant): Chronic inflammatory diseases affect millions of Americans each year, and have a significant medical, psychosocial, and economic impact on both the patient and on society. Multiple sclerosis is a chronic, degenerative neurological disorder involving immune-mediated inflammatory demyelinating processes, and is significantly exacerbated by comorbid conditions, such as stress and anxiety. Despite this knowledge, the mechanisms by which this occurs are not yet well understood. The studies in this proposal will test the highly novel and integrative hypothesis that the intestinal microbiota are involved in stressor-induced enhancement of systemic inflammation that leads to symptom exacerbation in an animal model of multiple sclerosis. We have made the exciting discovery that the intestinal microbiota are necessary for stressor-induced increases in splenic IL-1¿ to occur. This is important, because IL-1 plays a central role in the development of many chronic inflammatory diseases, including multiple sclerosis. How the microbiota lead to increased IL-1 during stressor exposure, as well as the effects on chronic inflammatory diseases, is not well understood. During repeated social defeat, commensal microbes can translocate from their primary niche to the interior of the body. Because there is accumulating evidence that neuroendocrine hormones, such as sympathetic nervous system-derived catecholamine hormones, can impact microbial populations, Aim 1 will test whether stressor-induced activation of the sympathetic nervous system leads to translocation of commensal microbiota. As further confirmation that microbial translocation is necessary for stressor-induced immunoenhancement to occur, Aim 2 will test the hypothesis that stressor-induced increases in splenic IL-1¿ are dependent upon both macrophage pattern recognition receptor signaling and inflammasome formation. Finally, to determine whether the microbiota contribute to stressor-induced exacerbation of a chronic disease, a widely used animal model of multiple sclerosis, namely experimental autoimmune encephalomyelitis (EAE) will be employed. The effects of repeated social defeat on EAE progression will be determined in germfree mice (i.e., mice that have never come into contact with commensal microbes) and conventional mice. By integrating the results of Aims 1, 2, and 3, we will identify novel mechanisms by which stressor exposure can exacerbate a chronic inflammatory disease. These findings would ultimately facilitate the rational design and use of microbiota-targeting therapeutics to treat chronic disease.