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

我们的实验室已经确定了细胞内补体活性在调节人类T细胞反应中的一个新的作用。在与美国国立卫生研究院和国际合作者的合作下，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。线粒体上的细胞内C5aR1信号是感染期间产生最佳IL-1β所必需的，也是无菌炎症所必需的。我们使用适当的高脂饮食CVD小鼠模型评估了这一观察的体内生物学意义，并注意到巨噬细胞内的C5aR1活性与小鼠和人类的CVD有关。此外，我们发现，通过与细胞通透性补体激活抑制剂(B因子抑制剂)孵育，我们可以使CVD患者单核细胞线粒体表达的C5aR1的高活性正常化。 髓系细胞自主产生C5也是保护脆弱患者免受机会性念珠菌感染所必需的。

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). Cell-autonomous C5 production in myeloid cells is also required for the protection against opportunistic Candida infections in vulnerable patients.