Blockade of PGK1 and ALDOA enhances bilirubin control of Th17 cells in Crohn's disease.

Abstract

Unconjugated bilirubin (UCB) confers Th17-cells immunosuppressive features by activating aryl-hydrocarbon-receptor, a modulator of toxin and adaptive immune responses. In Crohn's disease, Th17-cells fail to acquire regulatory properties in response to UCB, remaining at an inflammatory/pathogenic state. Here we show that UCB modulates Th17-cell metabolism by limiting glycolysis and through downregulation of glycolysis-related genes, namely phosphoglycerate-kinase-1 (PGK1) and aldolase-A (ALDOA). Th17-cells of Crohn's disease patients display heightened PGK1 and ALDOA and defective response to UCB. Silencing of PGK1 or ALDOA restores Th17-cell response to UCB, as reflected by increase in immunoregulatory markers like FOXP3, IL-10 and CD39. In vivo, PGK1 and ALDOA silencing enhances UCB salutary effects in trinitro-benzene-sulfonic-acid-induced colitis in NOD/scid/gamma humanized mice where control over disease activity and enhanced immunoregulatory phenotypes are achieved. PGK1 and/or ALDOA blockade might have therapeutic effects in Crohn's disease by favoring acquisition of regulatory properties by Th17-cells along with control over their pathogenic potential.

• Authors: Marta Vuerich, Na Wang, Jonathon J Graham, Li Gao, Wei Zhang, Ahmadreza Kalbasi, Lina Zhang, Eva Csizmadia, Jason Hristopoulos, Yun Ma, Efi Kokkotou, Adam S Cheifetz, Simon C Robson, Maria Serena Longhi
• Journal: Communications biology (Commun Biol) Vol. 5 Issue 1 Pg. 994 (09 21 2022) ISSN: 2399-3642 [Electronic] England
• PMID: 36131123 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Forkhead Transcription Factors
• Interleukin-10
• Phosphoglycerate Kinase
• Fructose-Bisphosphate Aldolase
• Benzene
• Bilirubin

Topics

• Animals
• Benzene (metabolism)
• Bilirubin
• Crohn Disease (genetics)
• Forkhead Transcription Factors (metabolism)
• Fructose-Bisphosphate Aldolase (metabolism)
• Humans
• Interleukin-10 (metabolism)
• Mice
• Mice, Inbred NOD
• Phosphoglycerate Kinase (antagonists & inhibitors)
• Th17 Cells