Objective Treg/Th17 imbalance plays an important role in rheumatoid arthritis (RA). Maresin 1 (MaR1) prompts inflammation resolution and regulates immune responses. We explored the effect of MaR1 on RA progression and investigated the correlation between MaR1 and Treg/Th17 balance.
Methods Both patients with RA and healthy controls were recruited into the study. Collagen-induced arthritis (CIA) model was constructed to detect the clinical score, histopathological changes and Treg/Th17 ratio. Purified naive CD4+ T-cells were used to study the effect of MaR1 on its differentiation process and microRNA microarray studies were performed to investigate MaR1 downstream microRNAs in this process. MicroRNA transfection experiments were conducted by lentivirus to verify the mechanism of MaR1 on Treg/Th17 balance.
Results Compared with controls, the MaR1 concentration was higher in the patients with inactive RA and lower in the patients with active RA. Expression of the Treg transcription factor FoxP3 was the highest in inactive RA and the lowest in active RA, while the Th17 transcription factor RORc showed a reverse trend. An inverse correlation was observed between the FoxP3/RORc ratio and Disease Activity Score 28. Intervention of MaR1 in the CIA model reduced joint inflammation and damage, and improved the imbalanced Treg/Th17 ratio. MaR1 increased Treg cells proportion while reduced Th17 cells proportion under specific differentiation conditions. Furthermore, miR-21 was verified as MaR1 downstream microRNA, which was upregulated by MaR1, modulating the Treg/Th17 balance and thus ameliorating the RA progression.
Conclusions MaR1 is a therapeutic target for RA, likely operating through effects on the imbalanced Treg/Th17 ratio found in the disease.
- rheumatoid arthritis
- t cells
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SJ, HC and YL contributed equally.
Handling editor Josef S Smolen
Contributors SJ, HC and JW conceived of the study and participated in its design and coordination. XY, HZ, JW, WS, QT, HC and JM collected samples, carried out ELISA assay and induced the CIA model. YL and JZ conducted UPLC-MS/MS experiment and data analysis. QT, JM, TZ and SY carried on the naive CD4+ T-cell differentiation experiment and flow cytometry. XY, WS and JW performed the statistical analysis. HZ, SJ and JW drafted and revised the manuscript. All authors read and approved the final manuscript. SJ, HC and YL made equal contributions to this work. All authors take responsibility for the integrity of the work.
Funding This project was supported by The National Key Research and Development Program of China (grant no. 2017YFC0909000); the Public Technology Applied Research Foundation of Zhejiang Province (grant no. LGF18H060009) and the National Natural Science Foundation (grant nos. 81472055, 81672129 and 81570076).
Competing interests None declared.
Patient consent Obtained.
Ethics approval The study protocol was approved by the Clinical Research Ethics Committees of the First Affiliated Hospital of Wenzhou Medical University (no. 2016157).
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it published Online First. The fourth affiliation has been updated.
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