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.
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.
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom; s.k.nanda@dundee.ac.uk p.cohen@dundee.ac.uk.
Sambit K
SK
Nanda
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom.
Marta
M
Lopez-Pelaez
Division of Immunology and Cell Signaling, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; and.
J Simon C
JS
Arthur
School of Veterinary Medicine, University of Glasgow, Glasgow G61 1QH, United Kingdom.
Francesco
0000-0003-1179-5788
F
Marchesi
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom; s.k.nanda@dundee.ac.uk p.cohen@dundee.ac.uk.
Philip
P
Cohen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D019943:Amino Acid Substitution; D000818:Animals; D003433:Crosses, Genetic; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D055879:Gene Knock-In Techniques; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology*; D007668:Kidney; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; C503281:Tnip2 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse