HSP90ß shapes the fate of Th17 cells with the help of glycolysis-controlled methylation modification.
Br J Pharmacol
; 181(20): 3886-3907, 2024 Oct.
Article
in En
| MEDLINE
| ID: mdl-38881036
ABSTRACT
BACKGROUND AND PURPOSE:
Ulcerative colitis (UC) is a refractory inflammatory disease associated with immune dysregulation. Elevated levels of heat shock protein (HSP) 90 in the ß but not α subtype were positively associated with disease status in UC patients. This study validated the possibility that pharmacological inhibition or reduction of HSP90ß would alleviate colitis, induced by dextran sulfate sodium, in mice and elucidated its mechanisms. EXPERIMENTALAPPROACH:
Histopathological and biochemical analysis assessed disease severity, and bioinformatics and correlation analysis explained the association between the many immune cells and HSP90ß. Flow cytometry was used to analyse the homeostasis and transdifferentiation of Th17 and Treg cells. In vitro inhibition and adoptive transfer assays were used to investigate functions of the phenotypically transformed Th17 cells. Metabolomic analysis, DNA methylation detection and chromatin immunoprecipitation were used to explore these mechanisms. KEYRESULTS:
The selective pharmacological inhibitor (HSP90ßi) and shHSP90ß significantly mitigated UC in mice and promoted transformation of Th17 to Treg cell phenotype, via Foxp3 transcription. The phenotypically-transformed Th17 cells by HSP90ßi or shHSP90ß were able to inhibit lymphocyte proliferation and colitis in mice. HSP90ßi and shHSP90ß selectively weakened glycolysis by stopping the direct association of HSP90ß and GLUT1, the key glucose transporter, to accelerate ubiquitination degradation of GLUT1, and enhance the methylation of Foxp3 CNS2 region. Then, the mediator path was identified as the "lactate-STAT5-TET2" cascade. CONCLUSION AND IMPLICATIONS HSP90ß shapes the fate of Th17 cells via glycolysis-controlled methylation modification to affect UC progression, which provides a new therapeutic target for UC.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HSP90 Heat-Shock Proteins
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Th17 Cells
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Glycolysis
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Mice, Inbred C57BL
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Br J Pharmacol
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Br. j. pharmacol
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British journal of pharmacology (Online)
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: