Abstract
Activated macrophages exhibiting diverse phenotypes and various functions contribute to the pathogenesis or amelioration of different diseases like cancer, inflammation, and infectious and autoimmune diseases. However, the mechanisms of macrophage polarization in inflamed joint and its effects on rheumatoid arthritis (RA) are still not clarified. This study is designed to explore the effects of cyclophilin A (CypA) on macrophage polarization and describe the underlying mechanisms. Collagen-induced arthritis (CIA) was employed to address the pro-arthritic effects of CypA. Flow cytometry was performed to investigate the populations of M1 and M2 macrophages in synovial tissues of the mice. Knockdown or overexpression of CypA macrophage cells was used to study the functions of CypA on macrophage polarization. Western blot was carried out to examine the potential signaling pathways. We found that CypA aggravated the severity of CIA in mice, as assessed by the increase of clinical score of inflammation, cartilage damage, and bone erosion. Moreover, the level of cytokines, such as IL-6, IL-1β, and IL-17, and the number of pro-inflammatory macrophages in synovial fluid were significantly elevated. In accordance with our observation, CypA dysregulation could actually influence the M1 macrophages polarization and pro-inflammatory cytokines production. Further mechanism study disclosed that CypA could regulate the transcriptional activity of NF-κB, the pivotal transcriptional factor regulating M1 polarization, dependent of its PPIase activity. Our findings provide evidence that PPIase CypA promoted macrophages polarization toward pro-inflammatory M1 phenotype via transcriptional activating NF-κB, thus leading to aggravated arthritis.
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Acknowledgements
The authors thank Banjun Ruan for providing valuable suggestions to our revised manuscript. This work was supported by the National Natural Science Foundation of China (Grant Numbers 81102259).
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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Wang L and Lu ZF had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design: Wang L and Lu ZF.
Acquisition of data: Zhai DS, Fu ZG, and Jia JF.
Analysis and interpretation of data: Wang L, Zhai DS, and Fu ZG.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the regional ethics committee from First Affiliated Hospital of Fourth Military Medical University and with the 1964 Helsinki Declaration and its later amendments. All procedures performed in studies involving animals were in accordance with the ethical standards of the Laboratory Animal Center of Fourth Military Medical University institution.
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Informed consent was obtained from all individual participants included in the study.
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Zhai Dongsheng and Fu Zhiguang are authors contribute equally to this work.
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Dongsheng, Z., Zhiguang, F., Junfeng, J. et al. Cyclophilin A Aggravates Collagen-Induced Arthritis via Promoting Classically Activated Macrophages. Inflammation 40, 1761–1772 (2017). https://doi.org/10.1007/s10753-017-0619-0
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DOI: https://doi.org/10.1007/s10753-017-0619-0