Tu107 - An Endogenous Metabolite, Itaconate Ameliorates Collagen-induced Arthritis by Inhibiting Fibroblast-like Synoviocytes Proliferation and Migration

Yuki Kudo – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Michihito Kono – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Kodai Sakiyama – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Shuhei Takeyama – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Ryo Hisada – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Yuichiro Fujieda – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Masaru Kato – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Olga Amengual – Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine – Hokkaido University; Tatsuya Atsumi – Professor, Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University

Abstract Text:

Introduction: Fibroblast-like synoviocytes (FLS) are critical players in the pathogenesis of rheumatoid arthritis (RA). A significant concern in the management of RA is increased susceptibility to infections. Itaconate (ITA) is an endogenous metabolite with anti-inflammatory and antimicrobial effects. This study aimed to identify the effect of ITA on FLS and its potential to treat RA.

Methods: FLS were isolated from synovial tissue of patients with RA. TNFα-treated FLS were cultured with ITA or PBS. The proliferation potency of FLS was evaluated by tetrazolium/formazan and BrdU assay. Cell migration was measured by scratch assay. An extracellular flux analyzer was utilised to evaluate mitochondrial oxidative phosphorylation. We performed RNA sequencing and metabolomics using TNFα-treated FLS with or without ITA. Finally, intraarticular injections of ITA or PBS into ankle joints were performed on rats with type II collagen-induced arthritis (CIA). Bone erosion scores were assessed by micro-CT.

Results: The proliferation of FLS measured by tetrazolium/formazan assay (p < 0.01), as well as BrdU assay (p < 0.01), was reduced by ITA. ITA also inhibited cell migration (p < 0.05). ITA decreased the maximal oxygen consumption rate. The results of RNA sequencing and metabolomics indicated that ITA altered FLS metabolism. Intraarticular injection of ITA reduced clinical arthritis score (p < 0.01) in the CIA model (two-way ANOVA test). The bone erosion score was reduced in the ITA-treated group (mean; 1.6 vs. 0.1, p< 0.01).

Conclusions: ITA inhibited the proliferation and cell migration of FLS and ameliorated CIA model. ITA could be a novel therapeutic agent of RA with a low risk of infections.