A Novel HDAC1-Selective Inhibitor Attenuates Autoimmune Arthritis by Inhibiting Inflammatory Cytokine Production

Wei Zhe, Naomi Hoshina, Yukihiro Itoh, Toshifumi Tojo, Takayoshi Suzuki, Koji Hase, Daisuke Takahashi

Research output: Contribution to journalArticlepeer-review

Abstract

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

Original languageEnglish
Pages (from-to)1364-1372
Number of pages9
JournalBiological & pharmaceutical bulletin
Volume45
Issue number9
DOIs
Publication statusPublished - 2022

Keywords

  • collagen antibody-induced arthritis
  • collagen-induced arthritis
  • histone deacetylase 1 inhibitor
  • macrophage
  • rheumatoid arthritis
  • T helper 17 cell

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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