IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells
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IL-11 has been detected in inflamed joints; however, its role in the pathogenesis of arthritis is not yet clear. Studies were conducted to characterize the expression and functional significance of IL-11 and IL-11Rα in rheumatoid arthritis (RA). IL-11 levels were elevated in RA synovial fluid (SF) compared to osteoarthritis (OA) SF and plasma from RA, OA and normal individuals (NLs). Morphologic studies established that IL-11 was detected in lining fibroblasts and macrophages in addition to sublining endothelial cells and macrophages at higher levels in RA compared to NL synovial tissues. Since IL-11Rα was exclusively expressed in RA fibroblasts and endothelial cells, macrophages were not involved in IL-11 effector function. Ligation of IL-11 to IL-11Rα strongly provoked fibroblast infiltration into RA joint, while cell proliferation was unaffected by this process. Secretion of IL-8 and VEGF from IL-11 activated RA fibroblasts was responsible for the indirect effect of IL-11 on endothelial cell transmigration and tube formation. Moreover, IL-11 blockade impaired RA SF capacity to elicit endothelial cell transmigration and tube formation. We conclude that IL-11 binding to endothelial IL-11Rα can directly induce RA angiogenesis. In addition, secretion of proangiogenic factors from migrating fibroblasts potentiated by IL-11 can indirectly contribute to RA neovascularization.
KeywordsIL-11 RA synovial tissue RA synovial fluid Endothelial migration and tube formation RA synovial tissue fibroblasts
This work was supported in part by awards from Department of Veteran’s Affairs MERIT Award 1I01BX002286, the National Institutes of Health R43AG057312, AR056099 and AR065778, funding provided by Department of Defense PR093477. We would like to acknowledge Dr. Rhonda Kineman for critically reviewing the paper and granting us access to use her laboratory microscope.
HAE, SS designed the research; HAE, MVV, ABE, ZC, SJK, KV, KP, SS performed the research; HAE, ZC, MVV, KV, MK, HMA, SJK, IBM, DAF, SS analyzed the data; SA, GZ: Provided reagents; all the authors contributed to writing the paper: Writing the paper.
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Conflict of interest
All the authors declare that they have no conflict of interest.
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