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.
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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

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Figure 5

TYK2 inhibition by small molecule or genetic mutation suppresses local IL-23–induced type 3 immunity in vivo.

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TYK2 inhibition by small molecule or genetic mutation suppresses local I...
(A) Overview of intradermal model of local IL-23 inflammation. IL-23 (400 ng) was administered by intradermal injection into one ear and PBS into the contralateral ear of mice for 3 consecutive days. For experiments involving NDI-031407, the indicated dose or 100 mg/kg was administered by gavage twice daily, starting 1 day before ear injections. (B) IL-17A assessed in whole-ear homogenate by Luminex assay. (C) Ears from a healthy mouse were enzymatically digested for analysis by flow cytometry. Dermal/epidermal T cell populations were identified in live CD45+CD3+ cells (top) and cytokines were assessed by staining for IL-17 and IL-22 in Il17aCre.Rosa26dTomato (IL-17AdTomato) reporter mice (bottom). (D–F) Brefeldin A was administered i.p. 5 hours before mouse sacrifice for intracellular cytokine analysis by flow cytometry. (D) Representative plots showing cytokine expression in dermal T cell populations of vehicle-treated mice. (E) Pooled data demonstrating in vivo IL-23–induced T cell IL-17A/IL-22 in the presence of NDI-031407. (F) In vivo IL-23–induced T cell IL-17A/IL-22 in mice expressing a kinase-inactive TYK2 (TYK2K923E). For all graphs, IL-23–treated ear compared with PBS-treated ear by paired t test; IL-23–treated ears from vehicle vs. NDI-031407 or WT vs. TYK2K923E compared by unpaired t test with Welch’s correction. For graphs in B, E, and F, each point represents data from a single mouse. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.