Nanda, S. K., Lopez-Pelaez, M., Arthur, J. S. C., Marchesi, F. and Cohen, P. (2016) Suppression of IRAK1 or IRAK4 catalytic activity, but not type 1 IFN signaling, prevents lupus nephritis in mice expressing a ubiquitin binding-defective mutant of ABIN1. Journal of Immunology, 197(11), pp. 4266-4273. (doi: 10.4049/jimmunol.1600788)
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Abstract
Polymorphisms in the TNIP1 gene encoding A20-binding inhibitor of NF-κB1 (ABIN1) predispose to lupus and other autoimmune diseases in at least eight human populations. We found previously that knock-in mice expressing a ubiquitin-binding–defective mutant of ABIN1 (ABIN1[D485N]) develop autoimmunity as they age and succumb to a disease resembling lupus nephritis in humans. In this article, we report that Flt3-derived dendritic cells from these mice overproduced type 1 IFNs upon stimulation with ligands that activate TLR7 or TLR9. However, crossing ABIN1[D485N] mice to IFNAR1-knockout mice that do not express the α-subunit of the type 1 IFNR did not prevent splenomegaly, the appearance of high serum levels of autoantibodies and other Igs, or liver inflammation and only reduced kidney inflammation modestly. In contrast, crossing ABIN1[D485N] mice to knock-in mice expressing catalytically inactive mutants of IRAK1 or IRAK4 prevented splenomegaly, autoimmunity, and liver and kidney inflammation. Our results support the notion that IRAK1 and/or IRAK4 are attractive targets for the development of drugs to prevent, and perhaps treat, lupus nephritis and other autoinflammatory diseases caused by the decreased ability of ABIN1 or other proteins to restrict the strength of MyD88 signaling.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by a U.K. Medical Research Council Programme Grant (MRC_MR/K000985/1) (to P.C.) and by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, and Merck-Serono. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Marchesi, Dr Francesco |
| Authors: | Nanda, S. K., Lopez-Pelaez, M., Arthur, J. S. C., Marchesi, F., and Cohen, P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| Journal Name: | Journal of Immunology |
| Publisher: | American Association of Immunologists |
| ISSN: | 0022-1767 |
| ISSN (Online): | 1550-6606 |
| Published Online: | 02 November 2016 |
| Copyright Holders: | Copyright © 2016 The Authors |
| First Published: | First published in Journal of Immunology 197(11):4266-4273 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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