Interleukin-23 as a therapeutic target for inflammatory myopathy

Natsuka Umezawa,Fumitaka Mizoguchi,Yoko Yoshihashi-Nakazato,Kimito Kawahata,Hitoshi Kohsaka,Nobuyuki Miyasaka,Naoki Kimura

doi:10.1038/s41598-018-23539-4

Natsuka Umezawa, Fumitaka Mizoguchi + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-23539-4

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Abstract

Current treatments of polymyositis and dermatomyositis (PM/DM) depend on non-specific immunosuppressants. This study was performed to elucidate the role of interleukin (IL)-23, as their possible therapeutic target. As was reported earlier in PM/DM patients, serum IL-23 levels were elevated in mice with C protein induced-myositis (CIM), a murine model of PM. IL-23 was expressed by macrophages in the PM/DM and CIM muscles and by dendritic cells and macrophages in the lymph nodes from the CIM mice. It was also expressed by macrophages in the chemically injured muscles, but not those recruited into the muscles by footpad injection of Freund’s complete adjuvant, demonstrating that IL-23 production should be associated with muscle damage. Genetic deletion of IL-23 as well as preventive and therapeutic administration of blocking antibodies against IL-23p19 subunit suppressed CIM. When lymph node cells from the CIM mice were transferred adoptively into naive wild type or IL-23p19 deficient recipient mice, both recipients developed myositis equally. Thus, elevated IL-23 should promote dendritic cells and macrophages to activate the autoaggressive T cells. Our findings suggest that IL-23 should mediate positive feedback loop from the muscle damage to the T cell activation and be a promising therapeutic target for autoimmune myositis.

Highlights

Polymyositis (PM) is a chronic inflammatory myopathy that impairs muscle functions to restrict daily activities of the affected patients
polymyositis and dermatomyositis (PM/DM) had higher concentrations of IL-23 in sera than healthy donors[9,10]. To study if this is the case with the C protein-induced myositis (CIM) mice, we examined serum from the CIM mice for concentrations of IL-23p19/IL-12p40 complexes 14 days after the immunization
IL-23p19 was expressed by CD68 + cells at the endomysium of the PM/DM and CIM muscles

Summary

Introduction

Polymyositis (PM) is a chronic inflammatory myopathy that impairs muscle functions to restrict daily activities of the affected patients. Our previous report disclosed that recruited macrophages into the muscle in response to the footpad CFA injection could not develop myositis on their own, but are responsible for “soil” activation by producing Interleukin (IL)-1 and tumor-necrosis factor alpha[6]. These cytokines are expressed by muscle fibers during homeostatic regeneration[7] and unpromising as therapeutic targets for PM/ dermatomyositis (DM) in clinical settings[8]. It expands Th17 cells and maintains their phenotype such as their cytokine production including IL-17A, which is www.nature.com/scientificreports/

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