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

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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.