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. 2024 Jul:264:110255.
doi: 10.1016/j.clim.2024.110255. Epub 2024 May 18.

Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models

Maria Tada  1 , Yuki Kudo  1 , Michihito Kono  2 , Masatoshi Kanda  3 , Shuhei Takeyama  1 , Kodai Sakiyama  1 , Hotaka Ishizu  4 , Tomohiro Shimizu  4 , Tsutomu Endo  4 , Ryo Hisada  1 , Yuichiro Fujieda  1 , Masaru Kato  1 , Olga Amengual  1 , Norimasa Iwasaki  4 , Tatsuya Atsumi  1
Affiliations
Free article

Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models

Maria Tada et al. Clin Immunol. 2024 Jul.
Free article

Abstract

Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.

Keywords: Fibroblast-like synoviocytes; Intracellular metabolism; Itaconate; Rheumatoid arthritis.

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Conflict of interest statement

Declaration of competing interest M. Kono has received research grants from GlaxoSmithKline, Mitsubishi Tanabe, Astellas, Sanofi, Taisho, Nippon Shinyaku, Taiju Life Social Welfare Foundation, Kowa, Terumo, Kyocera, Chugai, Mochida, Otsuka, Lotte, Hitachi, Takeda, and Yamazaki Baking, outside the submitted work. M. Kato received research grants and speaker's bureau from AbbVie, Janssen, Nippon Shinyaku, Novartis, Astellas, Eli Lilly, outside the submitted work. T. Atsumi has received grants, consulting fee or speakers' bureau from Astellas, Mitsubishi Tanabe, Chugai, Daiichi Sankyo, Pfizer, TEIJIN, Novartis, Sanofi, GlaxoSmithKline, AbbVie, AstraZeneca, Nippon Boehringer Ingelheim, Janssen, Gilead Sciences, Eli Lilly, ONO, Takeda, Alexion, Kyowa Kirin, Amgen, UCB Japan, and Esai, outside the submitted work. The other authors have no competing interests to declare.

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