The triterpenoid Nrf2 activator CDDO-Me decreases neutrophil senescence in a murine model of joint damage

Kristiana M. Amirova, Petya A. Dimitrova, Milena N. Leseva, Ivanka K. Koycheva, Albena T. Dinkova-Kostova, Milen I. Georgiev (Lead / Corresponding author)

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Abstract

The synthetic 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a potent activator of the erythroid 2-p45-derived factor 2, Nrf2, a leucine-zipper regulator of the antioxidant response. Herein, we investigated the effect of CDDO-Me on neutrophil function in a murine model of joint damage. Collagenase-induced osteoarthritis (CIOA) was initiated by the intra-articular injection of collagenase in the knee-joint cavity of Balb/c mice. CDDO-Me was administrated intra-articularly twice a week starting at day 7 post-CIOA, and its effect was evaluated at day 14. Neutrophils in blood and bone marrow (BM), cell apoptosis, necrosis, expression of C-X-C chemokine receptor 4 (CXCR4), beta-galactosidase (β-Gal), and Nrf2 levels were measured by flow cytometry. In vitro, CDDO-Me promoted cell survival, reduced cell necrosis, and increased Nrf2 levels by 1.6 times. It decreased surface CXCR4 expression and reduced the frequency of senescent β-Gal+CXCR4+ neutrophils by three times. In vivo, the degree of knee-joint damage in CIOA was correlated with upregulated CXCR4 on CD11b+ neutrophils. CDDO-Me improved the disease histological score, increased the levels of Nrf2, and downregulated surface CXCR4 on mature BM cells. Our data suggest that CDDO-Me may act as a potent regulator of neutrophil senescence during the progression of knee-joint damage.
Original languageEnglish
Article number8775
Number of pages24
JournalInternational Journal of Molecular Sciences
Volume24
Issue number10
DOIs
Publication statusPublished - 15 May 2023

Keywords

  • triterpenoids
  • CDDO-Me
  • Nrf2
  • neutrophils
  • senescence
  • CXCR4
  • CD11b

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