PGI2 Signaling Inhibits Glycolysis and Mitochondrial Respiration of CD4 Th2 Cells 2072

Description Prostaglandin I2 (PGI2) is a lipid mediator known to inhibit Th2 immune responses and allergic inflammation, but its role in regulating Th2 cell metabolism remains underexplored. Using the Seahorse assay, we evaluated the effects of PGI2 signaling on Th2 cell glycolysis and mitochondrial respiration. Our results show that cicaprost, a stable PGI2 analog, significantly reduced basal, maximal, and spare glycolytic capacities in wild-type (WT) Th2 cells, while these effects were absent in Th2 cells lacking the PGI2 IP receptor (IP KO). Cicaprost also impaired mitochondrial respiration and ATP production in WT Th2 cells, but not in IP KO cells, indicating that PGI2 signaling is essential for these metabolic changes. Further analysis revealed that cicaprost decreased GLUT1 expression and glucose uptake, suggesting PGI2 signaling inhibited glycolysis by reducing glucose availability. Metabolomic profiling of cicaprost-treated Th2 cells showed dose-dependent changes, with 126 downregulated and 233 upregulated metabolites showing over 2-fold significant changes compared to vehicle-treated cells. Pathway analysis of these altered metabolites suggested a shift from catabolism to anabolism in cicaprost-treated Th2 cells. These findings highlight PGI2 signaling as a key regulator of Th2 cell metabolism and suggest it could be a potential therapeutic target for managing Th2-driven allergic diseases. Funding Sources This study was supported by grants from the National Institutes of Health (R56 AI076411, R01 AI 070672, R01 AI 059108, GM 015431) and the Department of Veterans Affairs (1I01BX000624). Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)