Complement and Circadian Interactions in Inflammation and Immunity

炎症和免疫中的补体和昼夜节律相互作用

• 批准号: 10595544
• 负责人: Kristin Eckel Mahan
• 金额: $ 39万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595544
• 关键词: Affect; Anaphylatoxins; Animals; Applications Grants; Arrhythmia; Asthma; Behavioral; Biological Clocks; C3AR1 gene; Cells; Chronic; Chronic Disease; Circadian Dysregulation; Circadian Rhythms; Colitis; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Receptor; Data; Development; Diabetes Mellitus; Digestive System Disorders; Disease; Functional disorder; Gastrointestinal Diseases; Gastrointestinal tract structure; Genetic; Genetic Complementation Test; Goals; Gut associated lymphoid tissue; Health; Histologic; Host Defense; Hour; Human; Human Biology; Image; Immune; Immune System Diseases; Immune response; Immunity; Immunoassay; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Intestinal Content; Intestines; Jet Lag Syndrome; Knockout Mice; Knowledge; Light; Link; Lymph; Lymphatic; Lymphatic System; Lymphatic function; Lymphoid Tissue; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Obesity; Output; Pacemakers; Pathogenesis; Pathology; Patients; Peptides; Periodicity; Peripheral; Peyer' s Patches; Phase; Physiology; Population; Property; Receptor Signaling; Regulation; Risk; Role; Rotation; Signal Transduction; Source; System; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Time; Tissues; circadian; circadian pacemaker; complement system; cytokine; design; experimental study; gastrointestinal; in vivo; knockout animal; mouse model; mutant; new therapeutic target; novel; polarized cell; receptor; response; suprachiasmatic nucleus; tool; transcriptome sequencing

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.

摘要