Inhibition of Glycolysis Modifies Distinctive Metabolic and Immune Pathways Across Multiple Tissue Compartments Associated with B and T Follicular Helper Cells

Abstract

Abstract Systemic lupus erythematosus (SLE) is the most common form of lupus; however, only one new drug was approved for SLE in the last 60 years. Inhibition of glycolysis via 2-deoxyglucose (2DG), a competitive inhibitor of glucose-6-phosphate, has recently shown efficacy in attenuating tumor growth and reducing autoimmune pathology; however, the mechanism of this efficacy is somewhat unclear. To elucidate how 2DG longitudinally modulates pathways within the context of systemic lupus erythematosus (SLE), BXSB.Yaa IL15−/−,CD8−/− mice, an SLE model, were treated orally with 2DG for 96-hours or 4-weeks, after which the transcriptional profiles of 9 tissues (heart, hippocampus, hypothalamus, kidney, liver, prefrontal cortex, skeletal muscle, small intestine, and spleen) were analyzed using unsupervised clustering and weighted gene correlation network analysis. Principal component analysis showed mice clustered by tissue. Tissues correlated to B cells and T follicular helper cells grouped together according to their summary gene expression for modules treatment or treatment, in a time dependent manner, and three pathway groups, transcription, immune, and glucose, emerged. However, within each tissue cluster, pathways for each module were uniquely altered by treatment or treatment, in a time dependent manner, according to ANOVA. Furthermore, while most pathways identified were grouped into either immune or metabolic, there was little overlap of specific pathways identified between tissues. These results show that 2DG has a systemic impact altering immune and metabolic pathways, but in a tissue-specific manner. Ongoing work includes identifying genes that are potentially central to pathway alterations for follow-up analysis. Supported by the AAI Intersect Fellowship