m⁶A-Mediated Glycolysis by IL-37 Drives T Cell Metabolic Reprogramming to Regulate Colitis.

Area of Science:

• Immunology
• Molecular Biology
• Gastroenterology

Background:

• N6-methyladenosine (m⁶A) modification and T-cell metabolic reprogramming are key factors in inflammatory bowel disease (IBD).
• The role of the anti-inflammatory cytokine interleukin-37 (IL-37) in m⁶A-mediated metabolic regulation in IBD is not well understood.

Purpose of the Study:

• To investigate how IL-37 influences m⁶A modification and T-cell metabolism in the context of IBD.
• To elucidate the molecular mechanisms underlying IL-37's anti-inflammatory effects in IBD.

Main Methods:

• Investigated IL-37's effects on m⁶A levels and CD4+ T-cell metabolism in IBD models.
• Utilized cell signaling pathway analysis (IRAK4, JNK, NF-κB), gene expression analysis (METTL14, SLC2A1), and in vitro T-cell polarization assays.
• Employed adoptive transfer experiments with genetically modified T cells.

Main Results:

• IL-37 administration reduced colitis severity by decreasing global m⁶A levels and altering CD4+ T-cell metabolism.
• IL-37 signaling via SIGIRR inhibited IRAK4/JNK phosphorylation and NF-κB activation, leading to reduced METTL14 expression and m⁶A deposition.
• The IL-37/METTL14 pathway decreased m⁶A at SLC2A1's 3'UTR, destabilizing its mRNA, suppressing glycolysis, and shifting T-cell differentiation from Th1/Th17 to Th2.

Conclusions:

• The IL-37/SIGIRR-METTL14-m⁶A axis represents a novel regulator of T-cell metabolism in IBD.
• Targeting the IL-37 pathway and SLC2A1 may offer new therapeutic strategies for managing inflammatory bowel disease.