Background 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.
Methods 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.
Results Tissues correlated to activated autoreactive B cells grouped together according to their summary gene expression for modules treatment and two pathway groups, extracellular matrix/fibrin and immune, emerged. However, within each tissue cluster, pathways for each module were uniquely altered by treatment, according to ANOVA. Furthermore, while most pathways identified were grouped into either wound healing or immune, there was little overlap of specific pathways identified between tissues.
Conclusion These results show that 2DG has a systemic impact altering immune and wound pathways, but in a tissue-specific manner. Ongoing work includes identifying genes that are potentially central to pathway alterations for follow-up analysis.
Lay Summary 2-deoxyglucose inhibits glycolysis and has been shown to attenuate lupus. It is not well understood how 2DG affects the body systemically, so we assessed the effects of 2DG on nine tissues (heart, hippocampus, hypothalamus, kidney, liver, prefrontal cortex, skeletal muscle, small intestine, and spleen) in lupus prone mice. Each tissue responded to 2DG in a unique manner, indicating that acts on different pathways depending on the tissue being investigated.
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