The Walter and Eliza Hall Institute of Medical Research and the University of Melbourne, Parkville, Victoria, Australia.
The Walter and Eliza Hall Institute of Medical Research, the University of Melbourne and the Bio21 Institute, Parkville, Victoria, Australia.
Arthritis Rheumatol. 2019 Jan;71(1):50-62. doi: 10.1002/art.40670. Epub 2018 Nov 26.
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.
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.
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.
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.
源自组织生发中心（GC）的类转换高亲和力自身抗体的产生是许多自身免疫性炎症性疾病的标志，包括类风湿关节炎（RA）。TANK 结合激酶 1（TBK-1）是一种丝氨酸/苏氨酸激酶，参与诱导共刺激信号下游 GC 滤泡辅助 T（Tfh）细胞的成熟。我们进行这项研究是为了评估使用小分子抑制剂 WEHI-112 抑制 TBK-1 在抗体依赖性炎症性关节炎模型中的治疗潜力。
我们使用胶原诱导关节炎（CIA）、抗原诱导关节炎（AIA）和 K/BxN 血清转移诱导关节炎（STIA）模型，确定 WEHI-112 在 C57BL/6 和 DBA/1 小鼠关节炎的临床和组织学特征中的抑制作用。我们使用免疫组织化学方法来描述 CIA 发展过程中的 GC 群体，并用酶联免疫吸附试验来确定与 vehicle 治疗的小鼠相比，WEHI-112 治疗的小鼠中的 Ig 自身抗体水平。
WEHI-112 是一种工具化合物，对 TBK-1 具有半选择性，但对 IKKε 和 JAK2 也具有活性，可消除 TBK-1 依赖性干扰素（IFN）调节因子 3 的激活，并抑制体外 I 型 IFN 反应。在体内，WEHI-112 治疗选择性地消除了已建立的、抗体依赖性 CIA 的临床和组织学特征，但对抗体非依赖性 AIA 模型或 K/BxN STIA 几乎没有影响。与这些发现一致，WEHI-112 减少了致关节炎的 II 型胶原特异性 IgG1 和 IgG2b 抗体的产生。此外，WEHI-112 改变了 CIA 中的 GC Tfh 细胞表型和 GC B 细胞功能。
我们报告称，使用 WEHI-112 抑制 TBK-1 消除了抗体依赖性 CIA。由于 WEHI-112 未能抑制非抗体驱动的关节炎症，我们得出结论，该化合物的主要作用很可能是针对 GC 反应中 TBK-1 介导的机制。这种方法在 RA 和其他与 GC 相关的抗体驱动的炎症性疾病中可能具有治疗潜力。
