Therapeutic Effects of a TANK-Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen-Induced Arthritis

Cynthia Louis, Devi Ngo, Damian B. D'Silva, Jacinta Hansen, Louisa J Phillipson, Helene Jousset Sabroux, Patrizia M Novello, David Segal, Kate E Lawlor, Christopher J Burns, Ian Peter Wicks

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11 Citations (Scopus)


Objective: The production of class-switched high-affinity autoantibodies derived from organized germinal centers (GCs) is a hallmark of many autoimmune inflammatory diseases, including rheumatoid arthritis (RA). TANK-binding kinase 1 (TBK-1) is a serine/threonine kinase involved in the maturation of GC follicular helper T (Tfh) cells downstream of inducible costimulator signaling. We undertook this study to assess the therapeutic potential of TBK-1 inhibition using the small-molecule inhibitor WEHI-112 in antibody-dependent models of inflammatory arthritis. Methods: Using the models of collagen-induced arthritis (CIA), antigen-induced arthritis (AIA), and K/BxN serum-transfer–induced arthritis (STIA), we determined the effectiveness of WEHI-112 at inhibiting clinical and histologic features of arthritis in C57BL/6 and DBA/1 mice. We used immunohistochemistry to characterize GC populations during CIA development, and we used enzyme-linked immunosorbent assays to determine levels of Ig autoantibodies in WEHI-112–treated mice compared to vehicle-treated mice. Results: WEHI-112, a tool compound that is semiselective for TBK-1 but that also has activity against IKKε and JAK2, abolished TBK-1–dependent activation of interferon (IFN) regulatory factor 3 and inhibited type I IFN responses in vitro. In vivo, treatment with WEHI-112 selectively abrogated clinical and histologic features of established, antibody-dependent CIA, but had minimal effects on an antibody-independent model of AIA or on K/BxN STIA. In keeping with these findings, WEHI-112 reduced arthritogenic type II collagen–specific IgG1 and IgG2b antibody production. Furthermore, WEHI-112 altered the GC Tfh cell phenotype and GC B cell function in CIA. Conclusion: We report that TBK-1 inhibition using WEHI-112 abrogated antibody-dependent CIA. As WEHI-112 failed to inhibit non–antibody-driven joint inflammation, we conclude that the major effect of this compound was most likely the targeting of TBK-1–mediated mechanisms in the GC reaction. This approach may have therapeutic potential in RA and in other GC-associated autoantibody-driven inflammatory diseases.

Original languageEnglish
Pages (from-to)50-62
Number of pages13
JournalArthritis and Rheumatology
Issue number1
Publication statusPublished - 1 Jan 2019
Externally publishedYes

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