Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells
- Author(s)
- Kim, ML; Hardy, MY; Edgington-Mitchell, LE; Ramarathinam, SH; Chung, SZ; Russell, AK; Currie, I; Sleebs, BE; Purcell, AW; Tye-Din, JA; Wicks, IP;
- Details
- Publication Year 2021-12-17,Volume 24,Issue #12,Page 103509
- Journal Title
- iScience
- Abstract
- 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. © 2021 The Author(s)
- Publisher
- Elsevier
- Keywords
- Immune system; Molecular biology; Proteomics
- Research Division(s)
- Inflammation; Chemical Biology; Immunology
- PubMed ID
- 34934928
- Publisher's Version
- https://doi.org/10.1016/j.isci.2021.103509
- Open Access at Publisher's Site
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Creation Date: 2022-03-04 01:43:17
Last Modified: 2022-03-04 01:45:57