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

我们的实验室已经确定了一个新的作用，细胞内补体活性的调节人类T细胞反应。通过与NIH和国际合作者的合作，我们现在已经扩展了这一发现，并确定了细胞内C5 ar 1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C5 ar 1信号传导是感染期间最佳IL-1 β产生所必需的，但也是无菌炎症所必需的。我们目前正在使用适当的感染（念珠菌）和CVD小鼠模型评估这一观察结果的体内生物学意义。我们还在体外测试细胞渗透性C5抑制剂的作用，着眼于临床前模型的开发。 我们还在确定C5在单核细胞和T细胞中细胞内是如何被激活方面取得了进展，并正在对候选蛋白酶已被CRISP-Cas9技术删除的细胞进行最终实验。 更好地理解细胞内C5活性及其调节的关键作用将可能允许开发感染/慢性炎症的新疗法。

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 are currently assessing the in vivo biological significance of this observation using appropriate infection (candida) and CVD mouse models. We are also testing the effects of cell-permeable C5 inhibitors in vitro with an eye on the development of preclinical models. We have also made progress in defining how exactly C5 is activated intracellularly in monocytes and T cells and are performing final experiments with cells in which the candidate protease has been deleted by CRISP-Cas9 technology. The better understanding of the key roles of intracellular C5 activity and its regulation will potentially allow for the development of new therapies in infection/chronic inflammation.