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，打乱我们的生物钟对健康是有害的，夜班和轮班 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，通过对这些机制的理解 哪种昼夜节律的紊乱与疾病的发展有关，将对不断增长的 受到各种形式的昼夜节律干扰的人口的百分比。 昼夜节律受损和胃肠道炎症直接与几个主要 消化系统疾病，包括炎症性肠病(IBD)。虽然在昼夜节律中没有得到很好的研究 背景，补体激活和补体过敏毒素，C3a和C5a，已被牵连到 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。我们的初步数据显示，补体过敏毒素， 它们是在宿主防御和免疫反应中起关键作用的炎性多肽，可能提供了联系 昼夜节律紊乱和疾病易感性之间的关系，包括胃肠道疾病。这些数据 表明补体过敏性毒素(在多肽本身及其特异性水平上 受体)在体内受到直接的昼夜节律控制，并提供肠道淋巴的昼夜节律调节 活体内交换。这一应用的总体假设是，炎症和 补体系统的免疫(主要通过补体激活过敏毒素多肽)是 受到24小时生物钟紊乱的严重影响，导致免疫失调 反应和正常的淋巴功能。昼夜节律依赖性补体介导的功能障碍 炎症和免疫进而导致疾病病理增加，包括但不限于 与IBD等消化系统疾病的发展密切相关。为了支持这一假设，新奇的初步 数据显示，C5a调节肠道淋巴组织中的细胞含量和T细胞极化 组织以昼夜节律依赖的方式。此外，补体过敏性毒素的表达 昼夜节律依赖型外周神经节的Peyer‘s斑块缺乏C3aR和C5aR1受体 心律不齐。这些数据有力地表明，C3a/C3aR和C5a/C5aR1轴是一个新的和重要的 发生宿主淋巴免疫反应的昼夜节律门控的机制，以及它是先前的 昼夜节律紊乱和疾病病理之间未知但重要的联系，包括发育 炎症性肠病。利用昼夜节律突变模型，遗传和环境操纵 补充系统，最先进的成像和分子/生物分析工具，我们将描述 补体过敏性毒素以昼夜节律的方式调节肠道淋巴管的机制。

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.