TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis
Eric Gracey, … , Wenyan Miao, Robert D. Inman
Eric Gracey, … , Wenyan Miao, Robert D. Inman
Published March 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1863-1878. https://doi.org/10.1172/JCI126567.
View: Text | PDF
Research Article Autoimmunity

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

Abstract

Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23– and IL-17A–blocking antibodies for the treatment of SpA. Despite being able to provide symptomatic control, the current biologics do not prevent the fusion of joints in AS patients. Thus, there is an unmet need for disease-modifying drugs. Genetic studies have linked the Janus kinase TYK2 to AS. TYK2 is a mediator of type 3 immunity through intracellular signaling of IL-23. Here, we describe and characterize a potentially novel small-molecule inhibitor of TYK2 that blocked IL-23 signaling in vitro and inhibited disease progression in animal models of SpA. The effect of the inhibitor appears to be TYK2 specific, using TYK2-inactive mice, which further revealed a duality in the induction of IL-17A and IL-22 by IL-23. Specifically, IL-22 production was TYK2/JAK2/STAT3 dependent, while IL-17A was mostly JAK2 dependent. Finally, we examined the effects of AS-associated TYK2 SNPs on TYK2 expression and function and correlated them with AS disease progression. This work provides evidence that TYK2 inhibitors have great potential as an orally delivered therapeutic for SpA.

Authors

Eric Gracey, Dominika Hromadová, Melissa Lim, Zoya Qaiyum, Michael Zeng, Yuchen Yao, Archita Srinath, Yuriy Baglaenko, Natalia Yeremenko, William Westlin, Craig Masse, Mathias Müller, Birgit Strobl, Wenyan Miao, Robert D. Inman

×

Figure 4

TYK2 inhibition by small molecule suppresses systemic IL-23–induced type 3 immunity in vivo.

Options: View larger image (or click on image) Download as PowerPoint
TYK2 inhibition by small molecule suppresses systemic IL-23–induced type...
(A) Schematic of experiment. IL-23–expressing minicircle was administered by hydrodynamic delivery (HDD) to male B10RIII mice. At 1 week after minicircle administration, NDI-031407 was administered by gavage twice daily for 2 weeks. Clinical scoring for blepharitis, dermatitis, and arthritis was assessed every 3 days. (B) Pooled data for clinical scores (n = 5–8 per group). (C) Representative images of H&E-stained tissue at 3 weeks after minicircle administration; data pooled from each mouse shown in adjacent graphs. Scale bars: 200 μm for 4×, 100 μm for 10×, 50 μm for 20×. (D and E) At 3 weeks after minicircle administration, ear-draining (CLNs) and joint-draining (PLNs) lymph nodes were harvested for flow cytometric analysis of T cell subsets by transcription factor expression. (D) γδ T cell (TCRγδ+TCRβ–) frequency in draining lymph nodes. (E) Th17 cell frequency and activation status in the PLN. Data in B were analyzed by 2-way ANOVA with data paired over time. Average of minicircle/vehicle-treated mice compared with that of minicircle/NDI-031407–treated mice by Dunn’s post hoc test. In all other graphs, disease-free mice compared with minicircle/vehicle-treated mice by Mann-Whitney test and minicircle/NDI-031407 compared with minicircle/vehicle by Kruskal-Wallis test with Dunn’s post hoc test. For all scatter plots, each point represents a single mouse. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.