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

BACKGROUND: 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 h...

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Autores principales: Hu, Yiping, Xu, Bihua, He, Juan, Shan, Hongying, Zhou, Gengmin, Wang, Deli, Bai, Lu, Shang, Hongxi, Nie, Liping, Pan, Fan, Lan, Hui Yao, Wang, Qingwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947360/
https://www.ncbi.nlm.nih.gov/pubmed/36845150
http://dx.doi.org/10.3389/fimmu.2023.1104881
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author Hu, Yiping
Xu, Bihua
He, Juan
Shan, Hongying
Zhou, Gengmin
Wang, Deli
Bai, Lu
Shang, Hongxi
Nie, Liping
Pan, Fan
Lan, Hui Yao
Wang, Qingwen
author_facet Hu, Yiping
Xu, Bihua
He, Juan
Shan, Hongying
Zhou, Gengmin
Wang, Deli
Bai, Lu
Shang, Hongxi
Nie, Liping
Pan, Fan
Lan, Hui Yao
Wang, Qingwen
author_sort Hu, Yiping
collection PubMed
description BACKGROUND: 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.
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spelling pubmed-99473602023-02-24 Hypermethylation of Smad7 in CD4(+) T cells is associated with the disease activity of rheumatoid arthritis Hu, Yiping Xu, Bihua He, Juan Shan, Hongying Zhou, Gengmin Wang, Deli Bai, Lu Shang, Hongxi Nie, Liping Pan, Fan Lan, Hui Yao Wang, Qingwen Front Immunol Immunology BACKGROUND: 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. Frontiers Media S.A. 2023-02-09 /pmc/articles/PMC9947360/ /pubmed/36845150 http://dx.doi.org/10.3389/fimmu.2023.1104881 Text en Copyright © 2023 Hu, Xu, He, Shan, Zhou, Wang, Bai, Shang, Nie, Pan, Lan and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Hu, Yiping
Xu, Bihua
He, Juan
Shan, Hongying
Zhou, Gengmin
Wang, Deli
Bai, Lu
Shang, Hongxi
Nie, Liping
Pan, Fan
Lan, Hui Yao
Wang, Qingwen
Hypermethylation of Smad7 in CD4(+) T cells is associated with the disease activity of rheumatoid arthritis
title Hypermethylation of Smad7 in CD4(+) T cells is associated with the disease activity of rheumatoid arthritis
title_full Hypermethylation of Smad7 in CD4(+) T cells is associated with the disease activity of rheumatoid arthritis
title_fullStr Hypermethylation of Smad7 in CD4(+) T cells is associated with the disease activity of rheumatoid arthritis
title_full_unstemmed Hypermethylation of Smad7 in CD4(+) T cells is associated with the disease activity of rheumatoid arthritis
title_short Hypermethylation of Smad7 in CD4(+) T cells is associated with the disease activity of rheumatoid arthritis
title_sort hypermethylation of smad7 in cd4(+) t cells is associated with the disease activity of rheumatoid arthritis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947360/
https://www.ncbi.nlm.nih.gov/pubmed/36845150
http://dx.doi.org/10.3389/fimmu.2023.1104881
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