Pellerin, A., Yasuda, K., Cohen-Bucay, A. orcid.org/0000-0003-4951-7070 et al. (10 more authors) (2021) Monoallelic IRF5 deficiency in B cells prevents murine lupus. JCI Insight, 6 (15). ARTN e141395. ISSN 2379-3708
Abstract
Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model. In contrast, similar reduction of IRF5 expression in macrophages, monocytes, and neutrophils did not reduce disease severity. B cell receptor and TLR7 signaling synergized to promote IRF5 phosphorylation and increase IRF5 protein expression, with these processes being independently regulated. This synergy increased B cell-intrinsic IL-6 and TNF-α production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-α production in vitro and in vivo being substantially lower with loss of 1 allele of IRF5. Mechanistically, TLR7-dependent IRF5 nuclear translocation was reduced in B cells from IRF5-heterozygous mice. In addition, we show in multiple lupus models that IRF5 expression was dynamically regulated in vivo with increased expression in GC B cells compared with non-GC B cells and with further sequential increases during progression to plasmablasts and long-lived plasma cells. Overall, a critical threshold level of IRF5 in B cells was required to promote disease in murine lupus.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021, Pellerin et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
Keywords: | Germinal Center; B-Lymphocytes; Animals; Mice; Lupus Erythematosus, Systemic; Disease Models, Animal; Tumor Necrosis Factor-alpha; Interleukin-6; Signal Transduction; Autoimmunity; Gene Expression Regulation; Interferon Regulatory Factors; Gain of Function Mutation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Medical Research (LIMR) > Division of Haematology and Immunology |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 May 2024 08:39 |
Last Modified: | 10 May 2024 08:45 |
Published Version: | https://insight.jci.org/articles/view/141395 |
Status: | Published |
Publisher: | American Society for Clinical Investigation |
Identification Number: | 10.1172/jci.insight.141395 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:212377 |
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