Inverse regulation of GSDMD and GSDME gene expression during LPS-induced pyroptosis in RAW264.7 macrophage cells

GSDMD and GSDME, members of the gasdermin protein family, are involved in the formation of plasma membrane channels contributing to cell rupture during a certain type of necrosis called pyroptosis. GSDMD is activated in response to immunological stimulation such as lipopolysaccharides (LPS) treatment while GSDME is mainly involved in drug-induced tumor cell death. Here we show that the expression of the GSDMD gene increases significantly during LPS-induced pyroptosis in RAW264.7 murine macrophage cells. In contrast, GSDME expression is decreased in the same cells. The increasing effect of LPS on GSDMD expression was observed only when the cells were cultured in high glucose (4.5 g/l) medium, suggesting that glucose availability is important for this effect. The effect of LPS on GSDMD expression is abolished by 2-deoxyglucose (2DG), confirming that glycolysis plays crucial roles in the increasing effect of LPS. Small interference RNA-mediated knock down of GSDMD or overexpression of GSDME causes LPS-induced pyroptosis to take place through GSDME rather than through GSDMD. Taken together, LPS regulates GSDMD and GSDME expression in opposite directions through, at least in part, its effect on glycolysis. This transcriptional regulation may contribute to the execution of pyroptosis in a GSDMD-dependent manner.