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α-Difluoromethylornithine suppresses inflammatory arthritis by impairing myeloid-derived suppressor cells
Zhe Geng1, Bingxia Ming2, Shaoxian Hu2
1Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Objectives:
The chemopreventive drug α-difluoromethylornithine (DFMO) has been shown to have an antinociceptive effect on mechanical allodynia in inflammatory arthritis by directly inhibiting ornithine decarboxylase (ODC) and decreasing polyamine production in inflammatory sites. However, little is known about the effect of DFMO on the immune system of inflammatory arthritis. Here, we investigated the effect of DFMO in a well-established collagen-induced arthritis (CIA) mouse model and explored its effect on the immune system.
Methods:
The effect of DFMO on the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of CIA mice and their associations with disease severity, tissue inflammation and the levels of proinflammatory T-helper (Th) 17 cells in lymphoid tissues were investigated. The effects of DFMO on disease severity and Th17 cells were compared with those of antibody depletion of MDSCs. The arthritis severity was also evaluated by adoptive transfer of MDSCs derived from DFMO- or dH2O-treated mice.
Results:
In this study, we showed that both MDSCs and Th17 cells were significantly expanded in CIA mice. Treatment by DFMO at the onset of CIA suppressed the development of arthritis and decreased the frequency of MDSCs and Th17 cells. MDSC depletion by anti-Gr-1 mAb achieved a similar result, while combination treatment of both methods did not achieve a significant difference compared to either of the single treatments. In addition, the adoptive transfer of MDSCs derived from dH2O-treated mice with CIA restored the arthritis severity of CIA in mice treated with anti-Gr-1 mAb, while the transfer of MDSCs from DFMO-treated mice did not have such an effect.
Conclusions:
Our results identified DFMO as a potential therapeutic drug for the treatment of inflammatory arthritis.
Insights
The drug α-difluoromethylornithine (DFMO) reduces inflammatory arthritis by decreasing myeloid-derived suppressor cells (MDSCs) and T-helper 17 (Th17) cells. DFMO shows potential as a therapeutic for inflammatory arthritis.
Area of Science:
- Immunology
- Pharmacology
Background:
- Inflammatory arthritis is characterized by immune system dysregulation.
- α-difluoromethylornithine (DFMO) is a chemopreventive drug with known antinociceptive effects.
- The impact of DFMO on the immune system in inflammatory arthritis remains largely unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of DFMO in collagen-induced arthritis (CIA).
- To elucidate the effects of DFMO on immune cells, specifically myeloid-derived suppressor cells (MDSCs) and T-helper 17 (Th17) cells, in CIA.
Main Methods:
- Utilized a collagen-induced arthritis (CIA) mouse model.
- Administered DFMO and assessed its impact on disease severity, MDSC frequency, and Th17 cell levels.
- Compared DFMO treatment with antibody-mediated depletion of MDSCs.
- Evaluated arthritis severity via adoptive transfer of MDSCs from DFMO-treated or control mice.
Main Results:
- DFMO treatment significantly suppressed arthritis development in CIA mice.
- DFMO administration led to a decrease in both MDSC and Th17 cell frequencies.
- MDSC depletion mirrored the therapeutic effects of DFMO.
- Adoptive transfer of MDSCs from DFMO-treated mice did not restore arthritis severity, unlike those from control mice.
Conclusions:
- DFMO effectively mitigates inflammatory arthritis in a CIA mouse model.
- The therapeutic effects of DFMO are associated with the modulation of MDSCs and Th17 cells.
- DFMO presents a promising therapeutic candidate for treating inflammatory arthritis.
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