Foxo3a tempers excessive glutaminolysis in activated T cells to prevent fatal gut inflammation in the murine IL-10−/− model of colitis

• Published in: Cell death and differentiation Vol. 29; no. 3; pp. 585 - 599
• Main Authors: Hajjar, Stephanie, Nathan, Nayanan, Joseph, Julie, Mottawea, Walid, Ariana, Ardeshir, Pyatibrat, Sergey, Harper, Mary-Ellen, Alain, Tommy, Blais, Alexandre, Russell, Ryan C., Sad, Subash
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2022
• Subjects: 14; 38/77; 38/90; 631/250/1933; 631/250/256/2515; 64/60; 96/2; 96/21; 96/31; 96/95; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Colitis - genetics; Colitis - prevention & control; Forkhead Box Protein O3 - metabolism; Inflammation; Interleukin-10 - genetics; Life Sciences; Mechanistic Target of Rapamycin Complex 1 - genetics; Mice; Stem Cells; T-Lymphocytes
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-021-00876-y

Mutations in susceptibility alleles correlate with gut-inflammatory diseases, such as Crohn’s disease; however, this does not often impact the disease progression indicating the existence of compensatory genes. We show that a reduction in Foxo3a expression in IL-10-deficient mice results in a spontaneous and aggressive Crohn’s- like disease with 100% penetrance, which is rescued by deletion of myeloid cells, T cells and inhibition of mTORC1. In Foxo3a −/− IL-10 −/− mice, there is poor cell death of myeloid cells in the gut, leading to increased accumulation of myeloid and T cells in the gut. Myeloid cells express high levels of inflammatory cytokines, and regulatory T cells are dysfunctional despite increased abundance. Foxo3a signaling represses the transcription of glutaminase (GLS/GLS2) to prevent over-consumption of glutamine by activated T cells and its conversion to glutamate that contributes to the TCA cycle and mTORC1 activation. Finally, we show that Foxo3a restricts the abundance of colitogenic microbiota in IL-10-deficient mice. Thus, by suppressing glutaminolysis in activated T cells Foxo3a mediates a critical checkpoint that prevents the development of fulminant gut inflammatory disease.