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

Vuerich et al., Communications Biology, 2022, asked why Th17 cells from people with Crohn's disease ignore bilirubin. Bilirubin normally pushes a Th17 cell toward a regulatory state through the aryl hydrocarbon receptor, and in patient cells that does not happen. Profiling 180 metabolic genes put glycolysis at the centre: bilirubin lowered glycolysis and the glycolysis genes PGK1 and aldolase A in healthy Th17 cells, and did neither in patient cells, whose PGK1 and aldolase A were already high.

The test was to remove the two genes directly. Peripheral blood derived Th17 cells from patients and controls were given a self-delivering antisense oligonucleotide against PGK1 or against aldolase A at 10 μM for 72 hours, against a scramble control, with and without bilirubin. Silencing either gene restored the response: CD39, FOXP3 and IL-10 all rose, both as message and as the fraction of cells positive by flow cytometry. IL17A itself did not move. The effect was confined to Th17 cells, with no equivalent rise in Th1, Th2 or regulatory T cells from the same donors, and in patient CD4 cells the oligos trimmed the RORC positive fraction during polarization.

The work then moved into NOD/scid/gamma mice carrying human CD4 cells and given trinitrobenzene sulfonic acid colitis. A single intraperitoneal dose at 5.4 mg/kg alongside bilirubin gave a lower disease activity index, a longer colon, a lower histology score and less human CD3 infiltration than the scramble arm, with more FOXP3 positive cells in the spleen and fewer IL-17A positive cells in the mesenteric lymph node. The honest qualifier is in the same figure: the oligonucleotide on its own did not move disease activity or histology, so the benefit came from the combination. Note also that this paper never names its supplier, so the AUM attribution rests on the chemistry, the dose and a method citation rather than on a sentence.