TY - JOUR
T1 - The triterpenoid Nrf2 activator CDDO-Me decreases neutrophil senescence in a murine model of joint damage
AU - Amirova, Kristiana M.
AU - Dimitrova, Petya A.
AU - Leseva, Milena N.
AU - Koycheva, Ivanka K.
AU - Dinkova-Kostova, Albena T.
AU - Georgiev, Milen I.
N1 - Funding Information:
This research received funding from the European Union’s Horizon 2020 research and innovation program, project PlantaSYST (SGA No. 739582 under FPA No. 664620), and the BG05M2OP001-1.003-001-C01 project, financed by the European Regional Development Fund through the “Science and Education for Smart Growth” Operational Program. The work described in this article is facilitated by collaboration through COST Action CA20121, supported by the European Cooperation in Science and Technology ( www.cost.eu (accessed on 24 March 2023); https://benbedphar.org/about-benbedphar/ (accessed on 24 March 2023)).
Publisher Copyright:
© 2023 by the authors.
PY - 2023/5/15
Y1 - 2023/5/15
N2 - 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.
AB - 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.
KW - triterpenoids
KW - CDDO-Me
KW - Nrf2
KW - neutrophils
KW - senescence
KW - CXCR4
KW - CD11b
UR - http://www.scopus.com/inward/record.url?scp=85160380673&partnerID=8YFLogxK
U2 - 10.3390/ijms24108775
DO - 10.3390/ijms24108775
M3 - Article
C2 - 37240121
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 10
M1 - 8775
ER -