Glycolytic regulation of neuroinflammatory response: Role of monocarboxylate transporter 4

Abstract

Abstract Our study aimed to investigate the functional importance of the monocarboxylate transporter (MCT) 4 in vitro, in mouse primary mixed glial cells and in vivo, in mouse brain. Stimulation of primary mixed glial cells with LPS/IFNγ (LI)-induced the expression of MCT4. Inflammatory signals increase glycolysis and lactate production, which have been shown to sustain inflammatory response in immune cells. A real-time increase in glycolysis in LI-stimulated mixed glial cells was observed. We also found that IL-1β and NLRP3 expression was significantly increased in stimulated mixed glial cells, which are associated with chronic inflammatory diseases. MCT4 inhibitor, CHCA, significantly downregulated the proinflammatory response, glycolytic gene expression and real-time glycolysis in the primary mixed glial cells. As expected, CHCA blocked the release of lactate into the culture medium. Knockdown of MCT4 by using siRNA significantly attenuated the proinflammatory response suggesting that MCT4 could be a therapeutic target for neuroinflammatory diseases. Further, targeted metabolomics approach revealed that glycolytic intermediated, phosphoenolpyruvate and ribulose-1,5-bisphosphate, were significantly increased in primary mixed glial cells stimulated with LI, which were significantly decreased by CHCA treatment suggesting that intracellular accumulation of lactate attenuates glycolysis. CHCA treatment also diminished production of cytokines in the brain and spleen cells in an endotoxin mouse model. Importantly, we show that pharmacologic targeting of lactate transporters in glial cells might provide a novel and viable approach to resolve chronic inflammation in metabolic and neurodegenerative diseases.