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Identification of a Novel Toll‐like Receptor 7 Endogenous Ligand in Rheumatoid Arthritis Synovial Fluid That Can Provoke Arthritic Joint Inflammation
Author(s) -
Kim Seungjae,
Chen Zhenlong,
Essani Abdul B.,
Elshabrawy Hatem A.,
Volin Michael V.,
Volkov Suncica,
Swedler William,
Arami Shiva,
Sweiss Nadera,
Shahrara Shiva
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39544
Subject(s) - inflammation , immunology , endogeny , arthritis , synovial fluid , toll like receptor , rheumatoid arthritis , receptor , medicine , innate immune system , chemistry , immune system , pathology , osteoarthritis , alternative medicine
Objective Levels of Toll‐like receptor 7 (TLR‐7) are elevated in rheumatoid arthritis (RA), but the impact on RA is unknown because the endogenous ligand for TLR‐7 has not been identified. The aim of this study was to identify a TLR‐7 endogenous ligand and to determine its role in the pathogenesis of RA. Methods The presence of an endogenous TLR‐7 ligand, microRNA let‐7b (miR‐let‐7b), was examined by real‐time polymerase chain reaction (PCR) analysis. Using RA knockdown cells, TLR‐7–knockout mice, or antagonist, the specificity of miR‐let‐7b as a potential ligand for TLR‐7 was tested. The mechanism by which ligation of miR‐let‐7b to TLR‐7 promotes disease was investigated in RA myeloid cells by real‐time PCR, enzyme‐linked immunosorbent assay, and fluorescence‐activated cell sorting. We also established the effect of ectopic miR‐let‐7b expression on arthritic joint inflammation. Results We found that a TLR‐7 endogenous ligand resides mainly in RA synovial fluid macrophages. The GU‐rich domain in miR‐let‐7b was found to be essential for TLR‐7 ligation, since miR‐147, the positive control for GU, was able to stimulate TLR‐7+ myeloid cells, whereas miR‐124, the negative, non‐GU, control, was not. We demonstrated that miR‐let‐7b or exosomes containing miR‐let‐7b could transform the RA and/or mouse naive or antiinflammatory macrophages into inflammatory M1 macrophages via TLR‐7 ligation. Consistently, we showed that miR‐let‐7b provokes arthritis by remodeling naive myeloid cells into M1 macrophages via TLR‐7 ligation, since joint swelling and M1 macrophages are absent in TLR‐7–deficient mice. Conclusion The results of this study underscore the importance of miR‐let‐7b ligation to TLR‐7 in the joint during the effector phase of RA.