Cyclophilin A Aggravates Collagen-Induced Arthritis via Promoting Classically Activated Macrophages
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ORIGINAL ARTICLE
Cyclophilin A Aggravates Collagen-Induced Arthritis via Promoting Classically Activated Macrophages Zhai Dongsheng,1 Fu Zhiguang,2 Jia Junfeng,3 Lu Zifan,1,4 and Wang Li1,4
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 proarthritic 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. Abstract—
KEY WORDS: CypA; macrophage polarization; classically activated macrophages; rheumatoid arthritis. Zhai Dongsheng and Fu Zhiguang are authors contribute equally to this work.
INTRODUCTION
1
Rheumatoid arthritis is a systemic chronic inflammatory disorder that primarily targets synovial joints. Macrophage, the major source of proinflammatory cytokines, makes up around 30–40% of the cellular content in inflamed synovial tissues and plays a critical role in the development of rheumatoid arthritis (RA) [1]. The increased numbers of macrophages correlate well with the joint damage and clinical response to therapy. Activated macrophages exhibit significant functional heterogeneity and may be polarized into one of two main subtypes: classically activated, M1, and alternatively activated
State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, No. 169 West Changle Road, Xi’an, 710032, Shaanxi, People’s Republic of China 2 Institute of Stomatology, General Hospital of Chinese PLA, Beijing, 10085, People’s Republic of China 3 Departme
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