In:
Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-2-9)
Abstract:
Smad7 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. Methods Peripheral 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. Results Compared 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. Conclusion DNA 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.
Type of Medium:
Online Resource
ISSN:
1664-3224
DOI:
10.3389/fimmu.2023.1104881
DOI:
10.3389/fimmu.2023.1104881.s001
DOI:
10.3389/fimmu.2023.1104881.s002
DOI:
10.3389/fimmu.2023.1104881.s003
DOI:
10.3389/fimmu.2023.1104881.s004
DOI:
10.3389/fimmu.2023.1104881.s005
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2023
detail.hit.zdb_id:
2606827-8
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