The impact of GSK3β on the metabolism of IFNγ activated macrophages

Abstract

Abstract The activation of macrophages by IFNγ induces transcriptional and metabolic changes that enable the direct control of pathogens and improves interactions with T cells. In particular, IFNγ induces the expression of antigen presentation machinery like MHCII. Despite its central role in host immunity, the regulation of IFNγ-induced MHCII is poorly understood. Using CRISPR Cas9 screens we examined regulators of distinct IFNγ-mediated mechanisms in macrophages including MHCII. One key regulator found was the multifunctional kinase, GSK3β. Not only was GSK3β required to induce transcriptional activation of MHCII, but RNAseq analysis suggests broad changes to the IFNγ response in the absence of GSK3β. Recent work in our group suggests that changes in metabolism are essential for macrophages to respond to IFNγ. While GSK3β is known to directly modulate metabolism, its role in controlling metabolic changes following IFNγ activation remains unknown. Given that GSK3β interfaces with metabolic pathways like mTORC1 and glycolysis we hypothesize that the loss of GSK3β inhibits important metabolic shifts required for macrophages to effectively respond to IFNγ. Using a Seahorse Analyzer we are now determining how genetic or chemical inhibition of GSK3β changes the rate of glycolysis or oxidative phosphorylation following IFNγ stimulation. We will then directly target metabolic networks in the presence and absence of GSK3β to determine how these impact IFNγ responses including the expression of MHCII. Given the broad impact of GSK3β on several disease states, such as inflammatory disease and tumor progression, understanding the regulation of GSK3β has the potential to contribute to several aspects of human health.