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Arthritis Rheumatol. 2016 May;68(5):1099-110. doi: 10.1002/art.39544.

Identification of a Novel Toll-like Receptor 7 Endogenous Ligand in Rheumatoid Arthritis Synovial Fluid That Can Provoke Arthritic Joint Inflammation.

Author information

1
Jesse Brown VA Medical Center and University of Illinois at Chicago.
2
Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, Illinois.
3
University of Illinois at Chicago.

Abstract

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.

PMID:
26662519
PMCID:
PMC5221504
DOI:
10.1002/art.39544
[Indexed for MEDLINE]
Free PMC Article

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