Monocytes (macrophage precursor) are born in the bone marrow, where they rapidly are mobilized by danger signals to travel to tissue sites. Here they transform into macrophages and join other populations of specialized tissue-resident macrophages. A key hallmark of monocytes/macrophages is their phagocytic capability, making them the main “eaters” of the immune system. They are loaded with effector molecules, such as cytokines and digestive enzymes, enabling them to rapidly induce localized inflammation, digest tissue and participate in the clean-up process. They are critically involved in presenting antigens to adaptive immune cells and are indispensable for wound healing.
We are studying macrophages in three disease settings; (i) in atherosclerotic disease where they participate in tissue-injurious process in the atherosclerotic plaque; (ii) in rheumatoid arthritis, where they amplify inflammation and tissue damage in the joint; (iii) in vasculitis, where they are key components of wall-destructive granulomatous reactions and drive maladaptive repair responses.
By molecular analysis we have identified distinguishing features in patient-derived macrophages; with hypermetabolic activity emerging as a key identifier. In all three tissue-injurious diseases, macrophages are hypermetabolic, utilizing high concentrations of glucose. Functional outcomes include: excess mitochondrial activity causing high ATP and high ROS production. Mitochondrial hyperactivity, enabled by a molecular defect causing inactivation of the enzyme glycogen synthase kinase 3b, fuels a spectrum of functional capacities; including production of inflammatory cytokines, tissue-destructive cathepsins, expression of ligands to regulate pro-inflammatory T cells, etc.
Therapeutic approaches focusing on suppressing the tissue-damaging behavior of macrophages will need to dampen the hypermetabolic state of monocytes/macrophages.