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

National Heart, Lung, And Blood Institute

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Abstract

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. We are currently exploring whether macrophage-intrinsic C5 is needed for macrophage tissue residency and for compabting lung viral infections.