The role of the intracellular complement system - the complosome - in monocytes

细胞内补体系统（复合体）在单核细胞中的作用

• 批准号: 10699736
• 负责人: Claudia Kemper
• 金额: $ 39.79万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699736
• 关键词: Arteries; Biological; Biology; Brain; Cardiovascular Diseases; Cell Compartmentation; Cells; Collaborations; Complement; Complement Activation; Complement Factor B; Development; Disease; Event; Future; Goals; High Fat Diet; Human; Infection; Inflammation; International; Intervention; Laboratories; Medical; Mitochondria; Modeling; Molecular; Mus; Myeloid Cells; Pathway interactions; Patients; Permeability; Play; Production; Publishing; Regulation; Research; Role; Signal Transduction; Sterility; T cell response; United States National Institutes of Health; Work; complement system; in vivo; inhibitor; macrophage; monocyte; mouse model; neuroinflammation; novel

Our laboratory has identified a novel role for intracellular complement activity in the regulation of human T cell responses. In collaboration with groups from within the NIH and international collaborators, we have now extended this finding and defined a role for the intracellular C5aR1 also in normal human and mouse monocyte biology. Intracellular C5aR1 signaling on mitochondria is required for optimal IL-1beta production during infection but also sterile inflammation. We have assessed the in vivo biological significance of this observation using an appropriate high fat diet CVD mouse models and noted that intracellular C5aR1 activity in macrophages contributes to CVD in mice and humans. Further, we found that we can normalize hyper activity of mitochondrial expressed C5aR1 in monocytes from patients with CVD disease by incubation with a cell permeable complement activation inhibitor (Factor B inhibitor). The work is now published.

我们的实验室已经确定了细胞内补体活性在调节人类T细胞反应中的新作用。通过与NIH和国际合作者的合作，我们现在扩展了这一发现，并确定了细胞内C5aR1在正常人类和小鼠单核细胞生物学中的作用。细胞内线粒体上的C5aR1信号是感染期间最佳il -1 β产生所必需的，也是无菌炎症所必需的。我们使用适当的高脂肪饮食CVD小鼠模型评估了这一观察结果的体内生物学意义，并注意到巨噬细胞内C5aR1活性有助于小鼠和人类的CVD。此外，我们发现，通过细胞渗透性补体激活抑制剂（因子B抑制剂）孵育，我们可以使CVD患者单核细胞中线粒体表达的C5aR1的高活性正常化。