Figure 2.

Inflammatory Macrophages in Rheumatoid Synovitis. Bone marrow-derived macrophages that infiltrate into the arthritic joint enter an oxygen^lo, glucose^lo, ROS^hi, succinate^hi, fatty acid^hi, lactate^hi tissue environment. Inactivation of glycogen synthase kinase 3β (GSK-3β) in macrophages optimizes pyruvate import, enhancing mitochondrial activity. High oxidative phosphorylation increases ATP production and ROS release. ATP abundance promotes macrophage longevity. ROS facilitate the dimerization of the cytosolic enzyme pyruvate kinase M2 (PKM2), enabling nuclear translocation and STAT3 activation by the kinase. High mitochondrial activity supports the production of TNFα, IL-12, IL-23, IL-6 and IL-1β. Inflammatory macrophages trigger and sustain synovitis by modulating the function of neighboring T effector cells, endothelial cells, osteoclasts and synovial fibroblasts. NOX, NADPH oxidase; T_eff, T effector cell.