Metabolic Reprogramming of Pathogenic CD4 ⁺ T Helper Cells Attenuates Inflammatory Bowel Disease Pathogenesis

CD4 ⁺ T helper 1 (Th1) cells are involved in human inflammatory bowel disease (IBD) pathogenesis; however, mechanisms governing the persistent inflammatory function of these cells are unclear, leading us to examine how metabolism governs Th1 cell-induced IBD.

METHODS

Th1 cells supplemented with methyl pyruvate (MePyr) were analyzed to define how enforced mitochondrial pyruvate metabolism and subsequent glycogen synthase kinase 3β (GSK3β) deactivation reprogram cellular state. Re-analysis of the inflamed ileal single-cell RNA sequencing dataset from Crohn’s disease patients was performed to assess non-Treg CD4 ⁺ T cell metabolic gene signature. We assessed the capacity of a repurposed GSK3β inhibitor to restrain pathogenic CD4 ⁺ T cell-driven murine colitis.

RESULTS

Effector Th1 cells exhibit a distinct metabolic program exemplified by glucose-driven glycolysis but low mitochondrial respiration. MePyr deactivates GSK3β, glycolysis, and histone H3 acetylation on cytokine promoter region, resulting in reduced interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) expression in Th1 cells with concomitant gain of regulatory T cell-like program. GSK3β inhibition with LY2090314 mirrored the anti-inflammatory effect of MePyr in a manner reversible by acetate supplementation, implying that GSK3β potentially sustains glycolysis-derived acetyl-coenzyme A needed for histone acetylation and Th1 cell inflammatory response. Interleukin-21 exacerbates Th1 cell inflammatory response by maintaining a GSK3β-driven glycolytic program. The Th1 cell metabolic gene signature downregulated by MePyr or GSK3β inhibition in vitro is enriched in refractory Crohn’s disease patients. GSK3β inhibition with LY2090314 retrains T cell-induced colitis in mice.

CONCLUSIONS

MePyr impairs GSK3β-mediated glycolysis and Th1 cell immune response. GSK3β inhibition may mitigate Th1 cell-induced human IBD.