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The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling
Hydroxychloroquine (HCQ) is one of the most commonly prescribed immune-suppressants in treating rheumatoid arthritis (RA). Our previous research showed that HCQ suppressed RA development by inhibiting T follicular helper (Tfh) cells directly. Dendritic cells (DCs) serve as the link between innate an...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Authors. Published by Elsevier Masson SAS.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547638/ https://www.ncbi.nlm.nih.gov/pubmed/33049581 http://dx.doi.org/10.1016/j.biopha.2020.110848 |
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author | Han, Jiaochan Li, Xing Luo, Xiaoqing He, Juan Huang, Xuechan Zhou, Qingyou Han, Yanping Jie, Hongyu Zhuang, Jian Li, Yehao Yang, Fangyuan Zhai, Zeqing Wu, Shufan He, Yi Yang, Bin Sun, Erwei |
author_facet | Han, Jiaochan Li, Xing Luo, Xiaoqing He, Juan Huang, Xuechan Zhou, Qingyou Han, Yanping Jie, Hongyu Zhuang, Jian Li, Yehao Yang, Fangyuan Zhai, Zeqing Wu, Shufan He, Yi Yang, Bin Sun, Erwei |
author_sort | Han, Jiaochan |
collection | PubMed |
description | Hydroxychloroquine (HCQ) is one of the most commonly prescribed immune-suppressants in treating rheumatoid arthritis (RA). Our previous research showed that HCQ suppressed RA development by inhibiting T follicular helper (Tfh) cells directly. Dendritic cells (DCs) serve as the link between innate and acquired immunity. Whether HCQ suppressed Tfh cell through DCs was not clear. In current study, we found that HCQ efficiently inhibited CD86, chemokine (C-X-C motif) receptor 4 (CXCR4) expression and interferon-α (IFN-α) secretion of healthy donor derived purified DCs stimulated by RA patient serum. To mimic RA, collagen-induced arthritis (CIA) mouse model was used and treated with HCQ daily for fifty-four days prior to sacrifice. We found HCQ inhibited DC maturation and migration to lymph nodes (LNs), manifested as down-regulated expression of CD40, CD80, CD86, MHCII (I-A(q)) on LN DCs. In addition, HCQ reduced the level of chemokine receptor 7 (CCR7) and L-selectin on peripheral blood DCs and diminished percentage of LN DCs. Of note, HCQ only inhibited CpG ODN 1826-induced IL-12 secretion by bone marrow DCs (BMDCs) stimulated by various toll like receptor (TLR) agonists. Mechanistically, HCQ down-regulated the expression of TLR9 not only in healthy donor PBMC-derived DCs stimulated by RA patient serum, but also in LN DCs of CIA mice and CpG-activated BMDCs. Furthermore, arthritis scores in TLR9(−/−) mice were much lower than that in wild type mice with impaired maturity and migration capability of DCs. Collectively, activation of DCs contributes to the pathogenesis of RA and HCQ shows protective effects on RA by inhibition of DC activation via blocking TLR9. |
format | Online Article Text |
id | pubmed-7547638 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Authors. Published by Elsevier Masson SAS. |
record_format | MEDLINE/PubMed |
spelling | pubmed-75476382020-10-13 The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling Han, Jiaochan Li, Xing Luo, Xiaoqing He, Juan Huang, Xuechan Zhou, Qingyou Han, Yanping Jie, Hongyu Zhuang, Jian Li, Yehao Yang, Fangyuan Zhai, Zeqing Wu, Shufan He, Yi Yang, Bin Sun, Erwei Biomed Pharmacother Original Article Hydroxychloroquine (HCQ) is one of the most commonly prescribed immune-suppressants in treating rheumatoid arthritis (RA). Our previous research showed that HCQ suppressed RA development by inhibiting T follicular helper (Tfh) cells directly. Dendritic cells (DCs) serve as the link between innate and acquired immunity. Whether HCQ suppressed Tfh cell through DCs was not clear. In current study, we found that HCQ efficiently inhibited CD86, chemokine (C-X-C motif) receptor 4 (CXCR4) expression and interferon-α (IFN-α) secretion of healthy donor derived purified DCs stimulated by RA patient serum. To mimic RA, collagen-induced arthritis (CIA) mouse model was used and treated with HCQ daily for fifty-four days prior to sacrifice. We found HCQ inhibited DC maturation and migration to lymph nodes (LNs), manifested as down-regulated expression of CD40, CD80, CD86, MHCII (I-A(q)) on LN DCs. In addition, HCQ reduced the level of chemokine receptor 7 (CCR7) and L-selectin on peripheral blood DCs and diminished percentage of LN DCs. Of note, HCQ only inhibited CpG ODN 1826-induced IL-12 secretion by bone marrow DCs (BMDCs) stimulated by various toll like receptor (TLR) agonists. Mechanistically, HCQ down-regulated the expression of TLR9 not only in healthy donor PBMC-derived DCs stimulated by RA patient serum, but also in LN DCs of CIA mice and CpG-activated BMDCs. Furthermore, arthritis scores in TLR9(−/−) mice were much lower than that in wild type mice with impaired maturity and migration capability of DCs. Collectively, activation of DCs contributes to the pathogenesis of RA and HCQ shows protective effects on RA by inhibition of DC activation via blocking TLR9. The Authors. Published by Elsevier Masson SAS. 2020-12 2020-10-10 /pmc/articles/PMC7547638/ /pubmed/33049581 http://dx.doi.org/10.1016/j.biopha.2020.110848 Text en © 2020 The Authors Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Original Article Han, Jiaochan Li, Xing Luo, Xiaoqing He, Juan Huang, Xuechan Zhou, Qingyou Han, Yanping Jie, Hongyu Zhuang, Jian Li, Yehao Yang, Fangyuan Zhai, Zeqing Wu, Shufan He, Yi Yang, Bin Sun, Erwei The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling |
title | The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling |
title_full | The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling |
title_fullStr | The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling |
title_full_unstemmed | The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling |
title_short | The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling |
title_sort | mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: inhibition of dendritic cell functions via toll like receptor 9 signaling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547638/ https://www.ncbi.nlm.nih.gov/pubmed/33049581 http://dx.doi.org/10.1016/j.biopha.2020.110848 |
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