Histone deacetylases facilitate Th17-cell differentiation and pathogenicity in autoimmune uveitis via CDK6/ID2 axis.
J Adv Res
; 2024 Aug 05.
Article
em En
| MEDLINE
| ID: mdl-39107200
ABSTRACT
INTRODUCTION:
Autoimmune uveitis (AU) is a prevalent ocular autoimmune disease leading to significant visual impairment. However, underlying pathogenesis of AU required to develop more efficient therapy remain unclear.METHODS:
We isolated peripheral blood mononuclear cells (PBMCs) from AU patients and performed single-cell RNA sequencing (scRNA-seq). Besides, experimental autoimmune uveitis (EAU) model was established and treated with histone deacetylase inhibitor (HDACi) Belinostat or vehicle. We extracted immune cells from Blank, EAU, and HDACi-treated EAU mice and used scRNA-seq, flow cytometry, siRNA, specific inhibitors, and adoptive transfer experiments to explore the role of HDACs and its downstream potential molecular mechanisms in the immune response of EAU and AU.RESULTS:
We found highly expressed histone deacetylases (HDACs) family in AU patients and identified it as a key factor related to CD4+ effector T cell differentiation in the pathogenesis of AU. Our further studies showed that targeted inhibition of HDACs effectively alleviated EAU, restored its Th17/Treg balance, and reduced inflammatory gene expression, especially in CD4+ T cells. Post-HDACs inhibition, Treg proportions increased with enhanced immunomodulatory effects. Importantly, HDACs exhibited a positive promoting role on Th17 cells. Based on scRNA-seq screening and application of knock-down siRNAs and specific inhibitors in vitro and vivo, we identified CDK6 as a key downstream molecule regulated by HDAC1/3/6 through acetyl-histone H3/p53/p21 axis, which is involved in Th17 pathogenicity and EAU development. Additionally, HDACs-regulated CDK6 formed a positive loop with ID2, inducing PIM1 upregulation, promoting Th17 cell differentiation and pathogenicity, and correlates with AU progression.CONCLUSION:
Based on the screening of clinical samples and downstream molecular functional validation experiments, we revealed a driving role for HDACs and the HDACs-regulated CDK6/ID2 axis in Th17 cell differentiation and pathogenicity in AU, proposing a promising therapeutic strategy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
J Adv Res
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Egito