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bioRxiv · 10.1101/2025.04.15.649047

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

Mishra, S. K.·Abdelrahman, L. M.·Davidson, H. M.·Kim Lee, H. S.·Valenzuela-Perez, L.·Hassan, O. M.·Faubion, W. A.·Hirsova, P.·Bamidele, A. O.
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Abstract

BACKGROUND & AIMSCD4+ 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. METHODSTh1 cells supplemented with methyl pyruvate (MePyr) were analyzed to define how enforced mitochondrial pyruvate metabolism and subsequent glycogen synthase kinase 3{beta} (GSK3{beta}) deactivation reprogram cellular state. Re-analysis of the inflamed ileal single-cell RNA sequencing dataset from Crohns disease patients was performed to assess non-Treg CD4+ T cell metabolic gene signature. We assessed the capacity of a repurposed GSK3{beta} inhibitor to restrain pathogenic CD4+ T cell-driven murine colitis. RESULTSEffector Th1 cells exhibit a distinct metabolic program exemplified by glucose-driven glycolysis but low mitochondrial respiration. MePyr deactivates GSK3{beta}, glycolysis, and histone H3 acetylation on cytokine promoter region, resulting in reduced interferon-{gamma} (IFN-{gamma}) and tumor necrosis factor- (TNF-) expression in Th1 cells with concomitant gain of regulatory T cell-like program. GSK3{beta} inhibition with LY2090314 mirrored the anti-inflammatory effect of MePyr in a manner reversible by acetate supplementation, implying that GSK3{beta} 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 GSK3{beta}-driven glycolytic program. The Th1 cell metabolic gene signature downregulated by MePyr or GSK3{beta} inhibition in vitro is enriched in refractory Crohns disease patients. GSK3{beta} inhibition with LY2090314 retrains T cell-induced colitis in mice. CONCLUSIONSMePyr impairs GSK3{beta}-mediated glycolysis and Th1 cell immune response. GSK3{beta} inhibition may mitigate Th1 cell-induced human IBD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/649047v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@5b4acdorg.highwire.dtl.DTLVardef@18c03fforg.highwire.dtl.DTLVardef@15a75cforg.highwire.dtl.DTLVardef@1eca84d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Mishra, S. K., Abdelrahman, L. M., Davidson, H. M., Kim Lee, H. S., Valenzuela-Perez, L., Hassan, O. M., Faubion, W. A., Hirsova, P., Bamidele, A. O.. 2025-04-20. Metabolic Reprogramming of Pathogenic CD4+ T Helper Cells Attenuates Inflammatory Bowel Disease Pathogenesis. https://doi.org/10.1101/2025.04.15.649047

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