Role of Commensal Microbiota in Stressor-Induced Immunomodulation

描述(申请人提供)：慢性炎症性疾病每年影响数百万美国人，对患者和社会都有重大的医疗、心理和经济影响。多发性硬化症是一种慢性退行性神经疾病，涉及免疫介导的炎性脱髓鞘过程，并因应激和焦虑等共病而显著加重。尽管有这些知识，但发生这种情况的机制还没有被很好地理解。这项提案中的研究将检验高度新颖和综合的假设，即肠道微生物区系参与应激源诱导的全身炎症的增强，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，即肠道微生物区系是应激源诱导的脾IL-1增加所必需的。这一点很重要，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发挥着核心作用。微生物区系如何在应激源暴露期间导致IL-1增加，以及对慢性炎症性疾病的影响尚不清楚。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，目标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移位。为了进一步证实微生物易位是应激源诱导的免疫增强所必需的，AIM 2将测试应激源诱导的脾IL-1增加依赖于巨噬细胞模式识别受体信号和炎症体形成的假设。最后，为了确定微生物区系是否有助于应激源诱导的慢性疾病的恶化，将使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)。反复的社会失败对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)和常规小鼠身上确定。通过整合AIMS 1、2和3的结果，我们将确定应激源暴露可加剧慢性炎症性疾病的新机制。这些发现最终将有助于合理设计和使用微生物区系靶向疗法来治疗慢性病。

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.