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Published on: January 7, 2020
Macrophage migration inhibitory factor activates the inflammatory response in joint capsule fibroblasts following
Yuxin Zhang1,2, Shenji Lu1, Shuai Fan1
1Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Objectives:
Joint capsule fibrosis caused by excessive inflammation leading to post-traumatic joint contracture (PTJC). Fibroblasts trigger inflammation under the challenge of various proinflammatory cytokines. Macrophage migration inhibitory factor (MIF) is a prominent proinflammatory cytokine involved in inflammation- and fibrosis-associated pathophysiology, we investigated the role of MIF in PTJC.
Methods:
Using rat PTJC model and fibroblast inflammation model, we detected MIF expression in posterior joint capsule. Primary joint capsule fibroblasts (JFs) were used to investigate the effects of MIF on cell proliferation, migration and proinflammatory cytokines production. The mechanism of JF-mediated events was evaluated by qRT-PCR, western blot and immunoprecipitation. We screened the mRNA expression profile to identify gene candidates that mediate the effect of MIF on JFs.
Results:
MIF increased in posterior joint capsule following PTJC and co-localized with fibroblasts. Injection of MIF inhibitor significantly suppressed joint capsule inflammation and fibrosis. In vitro, MIF promoted JF proliferation, migration, and inflammation by regulating mitogen-activated protein kinase/nuclear factor-κB pathway through coupling with CD74. Transcriptome analysis revealed that lipid metabolism-related factors Pla2g2a, Angptl4, and Sgpp2, downstream of MIF/CD74, were potentially implicated in JF inflammation.
Conclusion:
MIF/CD74 axis elicited JF inflammation and may provide new therapeutic targets for joint capsule fibrosis in PTJC.
Insights
Macrophage migration inhibitory factor (MIF) drives joint capsule fibrosis and inflammation in post-traumatic joint contracture (PTJC). Targeting the MIF/CD74 pathway offers a promising therapeutic strategy for PTJC.
Area of Science:
- Biomedical Science
- Cell Biology
- Pathophysiology
Background:
- Post-traumatic joint contracture (PTJC) involves joint capsule fibrosis driven by inflammation.
- Fibroblasts and proinflammatory cytokines are key players in PTJC pathogenesis.
- Macrophage migration inhibitory factor (MIF) is a significant proinflammatory cytokine implicated in fibrosis.
Purpose of the Study:
- To investigate the role of MIF in the development of PTJC.
- To elucidate the mechanisms by which MIF influences joint capsule fibroblasts (JFs).
- To identify potential therapeutic targets for PTJC.
Main Methods:
- Utilized a rat PTJC model and a fibroblast inflammation model.
- Assessed MIF expression and its effects on JF proliferation, migration, and cytokine production.
- Employed qRT-PCR, western blot, immunoprecipitation, and transcriptome analysis to explore molecular mechanisms.
Main Results:
- MIF levels were elevated in the joint capsule post-PTJC and localized with fibroblasts.
- MIF inhibition significantly reduced joint capsule inflammation and fibrosis.
- MIF promoted JF proliferation and migration via the MIF/CD74-mediated MAPK/NF-κB pathway, influencing lipid metabolism genes.
Conclusions:
- The MIF/CD74 axis is crucial for JF inflammation in PTJC.
- Targeting the MIF/CD74 pathway presents a potential therapeutic avenue for joint capsule fibrosis.
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