Complement and Circadian Interactions in Inflammation and Immunity

摘要 昼夜节律（24小时）是人类生物学和生理学的重要组成部分。越来越多的 研究表明，我们的生物钟被打乱对健康有害， 工人患多种疾病的风险大大增加，包括癌症， 糖尿病、肥胖症和慢性炎症性肠病。因此，了解机制， 哪些昼夜节律紊乱与疾病的发展有关， 受到各种形式的昼夜节律破坏的人口百分比。 昼夜节律受损和胃肠道炎症与几种主要的 消化道疾病，包括炎症性肠病（IBD）。虽然没有很好地研究昼夜节律， 在上下文中，补体激活和补体过敏毒素C3 a和C5 a涉及 免疫功能障碍与许多疾病的发展密切相关，包括哮喘，癌症， 糖尿病和炎症性肠病。我们的初步数据表明补体过敏毒素， 在宿主防御和免疫反应中起关键作用的炎性肽， 昼夜节律紊乱和易患疾病，包括胃肠道疾病之间的联系。这些数据 表明补体过敏毒素（在肽本身以及它们的特异性抗原水平上） 受体）在体内处于直接的昼夜节律控制之下，并提供肠淋巴液的昼夜节律调节 体内交换本申请的总体假设是，炎症和炎症反应的调节是通过调节细胞内的细胞因子来实现的。 补体系统的免疫（主要通过补体激活过敏毒素肽）， 受24小时生物钟破坏的影响很大，导致免疫功能失调， 正常的淋巴功能。Th昼夜节律依赖性补体介导的功能障碍 炎症和免疫的增加反过来导致增加的疾病病理，包括但不限于 消化系统疾病如IBD的发展。为了支持这一假设，新的初步 数据显示，C5 a调节肠淋巴细胞中的细胞含量和T细胞极化， 以昼夜节律依赖的方式。此外，补体过敏毒素的表达 受体，C3 aR和C5 aR 1，在昼夜节律依赖性外周血淋巴结模型中缺乏 不好意思。这些数据有力地表明，C3 a/C3 aR和C5 a/C5 aR 1轴是一个新的和重要的， 宿主淋巴免疫应答的昼夜节律门控发生的机制，并且它是先前的免疫应答。 昼夜节律紊乱和疾病病理之间的未知但重要的联系，包括发展 炎症性肠病利用昼夜节律突变模型，基因和环境操纵， 补体系统，最先进的成像技术，以及分子/生物分析工具，我们将描述 补体过敏毒素以昼夜节律方式调节肠蠕动的机制。

ABSTRACT Circadian (24-hour) rhythms are an essential part of human biology and physiology. A growing number of studies have shown that disruption of our biological clock is detrimental to health, with night and rotating shift workers at substantially increased risk of developing numerous disease pathologies, including cancer, diabetes, obesity, and chronic inflammatory bowel disease. Thus, an understanding of the mechanisms by which circadian disruption are linked to disease development would be of great benefit to a growing percentage of the population subjected to circadian disruption of various forms. Impaired circadian rhythms and gastrointestinal inflammation are directly associated with several leading digestive tract disorders, including inflammatory bowel disease (IBD). While not well studied in a circadian context, complement activation and the complement anaphylatoxins, C3a and C5a, have been implicated in immune dysfunction are tightly linked to the development of numerous diseases, including asthma, cancer, diabetes, and inflammatory bowel disease. Our preliminary data indicate that the complement anaphylatoxins, which are phlogistic peptides with critical roles in host defense and the immune response, may provide the link between circadian disruption and vulnerability to diseases, including gastrointestinal disease. These data indicate that the complement anaphylatoxins (at the level of the peptides themselves as well as their specific receptors) are under direct circadian control in vivo and provide circadian modulation of intestinal lymph exchange in vivo. The overall hypothesis of this application is that the regulation of inflammation and immunity by the complement system (largely via the complement activation anaphylatoxin peptides) is greatly affected by disruption of the 24-hour circadian clock leading to dysregulation of the immune response and normal lymphatic function. Th circadian dependent complement mediated dysfunction of inflammation and immunity in turn leads to increased disease pathologies, including but not limited to the development of digestive disorders such as IBD. In support of this hypothesis, novel preliminary data are presented showing that C5a modulates the cellular content and T-cell polarization in gut lymphoid tissue in a circadian dependent manner. In addition, the expression of the complement anaphylatoxin receptors, C3aR and C5aR1, is deficient in Peyer’s patches in a model of circadian-dependent peripheral arrhythmicity. These data strongly suggest that the C3a/C3aR and C5a/C5aR1 axis is a novel and important mechanism by which circadian gating of the host lymphatic immune response occurs, and that it is a previously unknown yet important link between circadian disruption and disease pathologies, including the development of inflammatory bowel disease. Using circadian mutant models, genetic and environmental manipulation of the complement system, state of the art imaging, and molecular/bio-analytical tools we will delineate the mechanisms by which the complement anaphylatoxins modulate intestinal lymphatics in a circadian manner.