Hypermethylation of Smad7 in CD4+ T cells is associated with the disease activity of rheumatoid arthritis

Abstract

BackgroundSmad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whether Smad7-expressing CD4+ T cells and the methylation of Smad7 gene in CD4+ T cells contribute to the disease activity of RA in patients.MethodsPeripheral CD4+ T cells were collected from 35 healthy controls and 57 RA patients. Smad7 expression by CD4+ T cells were determined and correlated with the clinical parameters of RA including RA score and serum levels of IL-6, CRP, ESR, DAS28-CRP, DAS28-ESR, Swollen joints and Tender joints. Bisulfite sequencing (BSP-seq) was used to determine the DNA methylation in Smad7 promoter (-1000 to +2000) region in CD4+ T cells. In addition, a DNA methylation inhibitor, 5-Azacytidine (5-AzaC), was added to CD4+ T cells to examine the possible role of Smad7 methylation in CD4+ T cell differentiation and functional activity.ResultsCompared to the heath controls, Smad7 expression was significantly decreased in CD4+ T cells from RA patients and inversely correlated with the RA activity score and serum levels of IL-6 and CRP. Importantly, loss of Smad7 in CD4+ T cell was associated with the alteration of Th17/Treg balance by increasing Th17 over the Treg population. BSP-seq detected that DNA hypermethylation occurred in the Smad7 promoter region of CD4+ T cells obtained from RA patients. Mechanistically, we found that the DNA hypermethylation in the Smad7 promoter of CD4+ T cells was associated with decreased Smad7 expression in RA patients. This was associated with overreactive DNA methyltransferase (DMNT1) and downregulation of the methyl-CpG binding domain proteins (MBD4). Inhibition of DNA methylation by treating CD4+ T cells from RA patients with 5-AzaC significantly increased Smad7 mRNA expression along with the increased MBD4 but reduced DNMT1 expression, which was associated with the rebalance in the Th17/Treg response.ConclusionDNA hypermethylation at the Smad7 promoter regions may cause a loss of Smad7 in CD4+ T cells of RA patients, which may contribute to the RA activity by disrupting the Th17/Treg balance.

Mesenchymal Stromal Cells Over-expression Mutant IL-2 Enhance Treg Function in CIA Mice

“…RA, a prevalent immune system disease primarily affecting small and medium-sized joints, has its pathogenesis significantly influenced by the scarcity of Treg cells, a critical immunoregulatory cell type [5,6]. While Treg cell transplantation has shown efficacy in treating RA [40], this approach may encounter challenges such as low specificity and potential for non-specific rejection.…”

“…Regulatory T cells (Treg), a specialized subset of CD4 + CD25 + FOXP3 + T cells, play a pivotal role in suppressing autoimmune effector cells, thereby preventing autoimmune diseases and maintaining immune homeostasis [3,4]. A reduction in the proportion of Treg cells and their dysfunction are critical factors in the development and progression of rheumatoid arthritis [5,6]. Collagen-induced arthritis (CIA) mice, a widely recognized mouse model for rheumatoid arthritis, served as the experimental subjects in this study [7].…”

Global research hotspots and frontier trends of epigenetic modifications in autoimmune diseases: A bibliometric analysis from 2012 to 2022

“…Th17 cells play an important role in the onset and progression of RA. [ 77 ] Specific gene DNA methylation and histone modifications have been found to play a key role in the development and functional regulation of Th17 cells. For example, the DNA methylation level and histone acetylation level of the IL-17A gene are associated with disease activity in RA patients.…”

TGF‐β1 signaling and Smad7 control T‐cell responses in health and immune‐mediated disorders

“…The expression of Smad7 is significantly decreased in CD4 + T cells from rheumatoid arthritis patients, and its content is inversely correlated with rheumatoid arthritis activity scores, serum levels of inflammatory markers (i.e., IL‐6 and C‐reactive protein), and is associated with a high number of Th17 cells. Mechanistically, reduced expression of Smad7 in CD4 + T cells has been associated with DNA methyltransferase‐driven DNA hypermethylation in the Smad7 promoter [110]. Consistently, studies in mouse models of rheumatoid arthritis showed that loss of Smad7 resulted in activation of TGF‐β/Smad3 and NF‐κB pathways and predominant differentiation of Th17 cells, leading to synovial inflammation [108], whereas intraarticular overexpression of Smad7 improved experimental arthritis [111].…”