Therapeutic effects of a TBK1 kinase inhibitor in germinal center-driven, autoantibody-mediated inflammatory arthritis
- Louis, C; Ngo, D; D'Silva, DB; Hansen, J; Phillipson, L; Jousset, H; Novello, P; Segal, D; Lawlor, KE; Burns, CJ; Wicks, IP;
Publication Year 2019-01, Volume 71, Issue #1, Page 50-62
- Journal Title
- Arthritis & Rheumatology
- Publication Type
- Journal Article
- OBJECTIVE: The production of class-switched high-affinity autoantibodies derived from organised germinal centers (GC) is a hallmark of many autoimmune inflammatory diseases, including rheumatoid arthritis (RA). TANK-binding kinase 1 (TBK1) is a serine-threonine kinase involved in the maturation of GC T follicular B helper cells (TFH ) downstream of inducible T cell costimulator (ICOS) signalling. We therefore assessed the therapeutic potential of TBK1 inhibition using a small molecule inhibitor - known as WEHI-112 - in antibody dependent models of inflammatory arthritis. METHODS AND RESULTS: WEHI-112 - a tool compound, which is semi-selective for TBK1, but also has activity against IKKepsilon and JAK2 - abolished TBK1-dependent IRF3 activation and inhibited type I IFN responses in vitro. In vivo, treatment with WEHI-112 selectively abrogated clinical and histological features of established, antibody-dependent collagen-induced arthritis (CIA), but had minimal effects on an antibody-independent model of antigen-induced arthritis (AIA) or on K/BxN serum transfer-induced arthritis (STIA). In keeping with these findings, WEHI-112 reduced arthritogenic collagen type II (CII)-specific IgG1 and IgG2b antibody production. Furthermore, WEHI-112 altered the GC TFH phenotype and GC B cell function in CIA. CONCLUSION: In summary, we report that TBK1 inhibition using WEHI-112, albeit semi-selective for TBK1, abrogated antibody-dependent CIA, most likely explained by targeting TBK1-mediated mechanisms in the GC reaction as its major effect. This approach may have therapeutic potential in RA and in other GC-associated autoantibody-driven inflammatory diseases. This article is protected by copyright. All rights reserved.
- WEHI Research Division(s)
- Chemical Biology; Systems Biology And Personalised Medicine; Inflammation; Cancer And Haematology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-07-23 09:32:17Last Modified: 2020-02-03 01:16:53