Macrophage Function and the Role of GSK3

Abstract

Macrophages are present in nearly all vertebrate tissues, where they respond to a complex variety of regulatory signals to coordinate immune functions involved in tissue development, metabolism, homeostasis, and repair. Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed protein kinase that plays important roles in multiple pathways involved in cell metabolism. Dysregulation of GSK3 has been implicated in several prevalent metabolic disorders, and recent findings have highlighted the importance of GSK3 activity in the regulation of macrophages, especially with respect to the initiation of specific pathologies. This makes GSK3 a potential therapeutic target for the development of novel drugs to modulate immunometabolic responses. Here, we summarize recent findings that have contributed to our understanding of how GSK3 regulates macrophage function, and we discuss the role of GSK3 in the development of metabolic disorders and diseases.

Keywords: atherosclerosis; glycogen synthase kinase (GSK)-3; inflammatory response; macrophage function; molecular mechanisms.

Figure 1

Macrophage: polarization, function, and associated diseases. Three main families of receptors regulate macrophage polarization and function. These are (1) the toll-like receptors (TLRs) that signal through nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and AP-1, (2) the interferon receptor (IFNR) and interleukin (IL)-4 receptors that signal through signal transducer and activator of transcriptions (STATs), and (3) the nuclear receptors. Macrophage stimulated with lipopolysaccharide (LPS) and/or interferon-gamma (IFNγ) polarize to pro-inflammatory (M1) macrophages. Stimulation with IL4 induce polarization to anti-inflammatory (M2) macrophages. Regulation is important for proper physiological responses; however, dysregulation can contribute to the pathogenesis of diseases.

Figure 2

GSK3α/β: regulation, cellular functions and diseases. Three cellular signaling pathways are directly involved in GSK3α/β regulation: (1) insulin binds to the insulin receptor and activates the PI3-Akt pathway leading to GSK3α/β inhibition; (2) endoplasmic reticulum stress (ER stress) signaling and/or unfolded protein response (UPR) activation promotes the activation of GSK3α/β through the endoplasmic reticulum kinase (PERK) pathway; and (3) Wnt ligands bind to the Frizzled receptor and induces the formation of a complex of the scaffold protein axin, APC, CK1 and the kinase Dishevelled, which phosphorylates and inactivates GSK3α/β. The complex interplay between these pathways regulates the network of signaling pathways that modulate cell viability and metabolism.

Figure 3

A summary of the GSK3α/β signaling pathways in macrophage functions and related diseases. In macrophages GSK3α/β can be activated or inactivated by different upstream signaling pathways. GSK3α/β has a large number of downstream substrates that regulate a variety of different downstream signaling pathways to control macrophage phenotype and function. Dysregulation of one or more of these pathways has been implicated in the development of several different disorders/diseases.