Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells
© 2021 The Author(s)..
Although hydroxychloroquine (HCQ) has long been used to treat autoimmune diseases, its mechanism of action remains poorly understood. In CD4 T-cells, we found that a clinically relevant concentration of HCQ inhibited the mitochondrial antioxidant system triggered by TCR crosslinking, leading to increased mitochondrial superoxide, impaired activation-induced autophagic flux, and reduced proliferation of CD4 T-cells. In antigen-presenting cells, HCQ also reduced constitutive activation of the endo-lysosomal protease legumain and toll-like receptor 9, thereby reducing cytokine production, but it had little apparent impact on constitutive antigen processing and peptide presentation. HCQ's effects did not require endo-lysosomal pH change, nor impaired autophagosome-lysosome fusion. We explored the clinical relevance of these findings in patients with celiac disease-a prototypic CD4 T-cell-mediated disease-and found that HCQ limits ex vivo antigen-specific T cell responses. We report a T-cell-intrinsic immunomodulatory effect from HCQ and suggest potential re-purposing of HCQ for celiac disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
iScience - 24(2021), 12 vom: 17. Dez., Seite 103509 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kim, Man Lyang [VerfasserIn] |
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| Anmerkungen: |
Date Revised 23.12.2021 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.isci.2021.103509 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM334709180 |
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| 520 | |a © 2021 The Author(s). | ||
| 520 | |a Although hydroxychloroquine (HCQ) has long been used to treat autoimmune diseases, its mechanism of action remains poorly understood. In CD4 T-cells, we found that a clinically relevant concentration of HCQ inhibited the mitochondrial antioxidant system triggered by TCR crosslinking, leading to increased mitochondrial superoxide, impaired activation-induced autophagic flux, and reduced proliferation of CD4 T-cells. In antigen-presenting cells, HCQ also reduced constitutive activation of the endo-lysosomal protease legumain and toll-like receptor 9, thereby reducing cytokine production, but it had little apparent impact on constitutive antigen processing and peptide presentation. HCQ's effects did not require endo-lysosomal pH change, nor impaired autophagosome-lysosome fusion. We explored the clinical relevance of these findings in patients with celiac disease-a prototypic CD4 T-cell-mediated disease-and found that HCQ limits ex vivo antigen-specific T cell responses. We report a T-cell-intrinsic immunomodulatory effect from HCQ and suggest potential re-purposing of HCQ for celiac disease | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Ramarathinam, Sri H |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Shan Zou |e verfasserin |4 aut | |
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