Suppression of IRAK1 or IRAK4 catalytic activity, but not type1 IFN signaling, prevents lupus nephritis in mice expressing a ubiquitin binding-defective mutant of ABIN1

Sambit K. Nanda (Lead / Corresponding author), Marta Lopez-Pelaez, J. Simon C. Arthur, Francesco Marchesi, Philip Cohen (Lead / Corresponding author)

Research output: Contribution to journalArticle

20 Citations (Scopus)
182 Downloads (Pure)

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 different 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. Here we report that Flt3-derived dendritic cells from these mice overproduced Type1 IFNs upon stimulation with ligands that activate TLR7 or TLR9. However, crossing the ABIN1[D485N] mice to IFNAR1 knock-out mice that do not express the α-subunit of the Type1 IFN receptor, did not prevent splenomegaly, the appearance of high serum levels of auto-antibodies and other Igs, or liver inflammation, and only reduced kidney inflammation modestly. In contrast, crossing the ABIN1[D485N] mice to knock-in mice expressing catalytically inactive mutants of IRAK1 or IRAK4 prevented splenomegaly, autoimmunity, 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 auto-inflammatory diseases caused by decreased ability of ABIN1 or other proteins to restrict the strength of MyD88 signaling.
Original languageEnglish
Pages (from-to)4266-4273
Number of pages8
JournalJournal of Immunology
Volume197
Issue number11
Early online date2 Nov 2016
DOIs
Publication statusPublished - 1 Dec 2016

Fingerprint Dive into the research topics of 'Suppression of IRAK1 or IRAK4 catalytic activity, but not type1 IFN signaling, prevents lupus nephritis in mice expressing a ubiquitin binding-defective mutant of ABIN1'. Together they form a unique fingerprint.

  • Projects

    Profiles

    No photo of Philip Cohen

    Cohen, Philip

    • MRC PPU - Research Professor & Personal Chair in Enzymology

    Person: Academic

    Cite this