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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: Immunol Rev. 2020 Jan 27;294(1):177–187. doi: 10.1111/imr.12838

Figure 8. Hypermetabolic macrophages in rheumatoid arthritis.

Figure 8.

In RA macrophages, Glycogen Synthase Kinase 3β (GSK-3β) is inactivated, enhancing the activity of the mitochondrial electron transport chain. GSK-3β is a constitutively active protein kinase that negatively regulates glucose homeostasis. Inactivation of GSK3β results in the activation of oxidative phosphorylation, enhanced ATP production and increased ROS release. Functional consequences include longevity of highly activated macrophages. ROS facilitate the dimerization of the cytosolic enzyme pyruvate kinase M2 (PKM2) and nuclear translocation of the enzyme, where it activates STAT3. Several pro-inflammatory activities of macrophages are dependent on GSK-3β inactivation and enhanced ROS release; such as the production of cathepsin K, IL-1β, and IL-6.