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

The Journal of Clinical Investigation
Eric GraceyRobert D Inman

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 correla...Continue Reading

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Citations

Jul 15, 2020·Nature Reviews. Rheumatology·Eric GraceyDirk Elewaut
Jul 23, 2020·Immunology·Aniruddha Voruganti, Paul Bowness
Apr 2, 2020·Nature Reviews. Rheumatology·Sarah Onuora
Sep 16, 2020·Cell Death and Differentiation·Andrea PoelzlBirgit Strobl
Jan 8, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jiasi WuXianli Meng
Nov 17, 2020·Frontiers in Immunology·Ariane HammitzschPhilipp Moog
Apr 6, 2021·Mediators of Inflammation·Narendra KumarJayshree Mishra
Apr 6, 2021·Frontiers in Immunology·Dennis McGonagleCharlie Bridgewood
Apr 25, 2021·Current Rheumatology Reports·Akihiro Nakamura, Nigil Haroon
Jun 12, 2021·Nature Reviews. Rheumatology·Daniele MauroFrancesco Ciccia
Jul 1, 2021·Nature Reviews. Rheumatology·Yuriy BaglaenkoSoumya Raychaudhuri
Jun 22, 2021·Frontiers in Immunology·Angela CeribelliCarlo Selmi
Jul 17, 2021·Frontiers in Immunology·Mohamed MandourMarleen G H van de Sande
Sep 29, 2021·Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG·Kamran GhoreschiDiamant Thaçi

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Methods Mentioned

BETA
PCR
flow cytometry
FACS
targeted mutation
biopsy

Software Mentioned

PrimeFlow

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