Inducible deletion of Ezh2 in CD4+ T cells inhibits kidney T cell infiltration and prevents interstitial nephritis in MRL/lpr lupus-prone mice.
Xiaoqing ZhengMikhail G DozmorovLuis EspinozaMckenna M BowesSheldon BastackyAmr Hakam SawalhaPublished in: bioRxiv : the preprint server for biology (2024)
Systemic lupus erythematosus is a remitting relapsing autoimmune disease characterized by autoantibody production and multi-organ involvement. T cell epigenetic dysregulation plays an important role in the pathogenesis of lupus. We have previously demonstrated upregulation of the key epigenetic regulator EZH2 in CD4+ T cells isolated from lupus patients. To further investigate the role of EZH2 in the pathogenesis of lupus, we generated a tamoxifen-inducible CD4+ T cell Ezh2 conditional knockout mouse on the MRL/lpr lupus-prone background. We demonstrate that Ezh2 deletion abrogates lupus-like disease and prevents T cell differentiation. Single-cell analysis suggests impaired T cell function and activation of programed cell death pathways in EZH2-deficient mice. Ezh2 deletion in CD4+ T cells restricts TCR clonal repertoire and prevents kidney-infiltrating effector CD4+ T cell expansion and tubulointerstitial nephritis, which has been linked to end-stage renal disease in patients with lupus nephritis.
Keyphrases
- systemic lupus erythematosus
- disease activity
- end stage renal disease
- long noncoding rna
- chronic kidney disease
- long non coding rna
- peritoneal dialysis
- rheumatoid arthritis
- multiple sclerosis
- cell death
- dna methylation
- gene expression
- newly diagnosed
- mouse model
- ejection fraction
- type diabetes
- dendritic cells
- signaling pathway
- immune response
- adipose tissue
- high throughput
- insulin resistance