The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

Abstract

Immune cells must be able to adjust their metabolic programs to effectively carry out their effector functions. Here, we show that the ER stress sensor IRE1 and its downstream transcription factor XBP1 enhance the upregulation of glycolysis in classically activated macrophages (CAM). The IRE1-XBP1 signaling axis supports this glycolytic switch in macrophages when activated by LPS stimulation or infection with the intracellular bacterial pathogen Brucella abortus. Importantly, these different inflammatory stimuli have distinct mechanisms of IRE1 activation; while TLR4 supports glycolysis under both conditions, TLR4 is required for activation of IRE1 in response to LPS treatment but not B. abortus infection. Though IRE1 and XBP1 are necessary for maximal induction of glycolysis in CAM, activation of this pathway is not sufficient to increase the glycolytic rate of macrophages, indicating that the cellular context in which this pathway is activated ultimately dictates the cells metabolic response and that IRE1 activation may be a way to fine-tune metabolic reprogramming. IMPORTANCEThe immune system must be able to tailor its response to different types of pathogens in order to eliminate them and protect the host. When confronted with bacterial pathogens, macrophages, frontline defenders in the immune system, switch to a glycolysis-driven metabolism to carry out their antibacterial functions. Here, we show that IRE1, a sensor of ER stress, and its downstream transcription factor XBP1 support glycolysis in macrophages during infection with Brucella abortus or challenge with Salmonella LPS. Interestingly, these stimuli activate IRE1 by independent mechanisms. While the IRE1-XBP1 signaling axis promotes the glycolytic switch, activation of this pathway is not sufficient to increase glycolysis in macrophages. This study furthers our understanding of the pathways that drive macrophage immunometabolism and highlights a new role for IRE1 and XBP1 in innate immunity.