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Clin Immunol. 2017 Mar;176:12-22. doi: 10.1016/j.clim.2016.12.005. Epub 2016 Dec 27.

Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus.

Author information

1
Division of Rheumatology and Immunology, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
2
Department of Molecular Genetics, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
3
School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, and Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
4
Department of Microbial Infection and Immunity, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
5
Department of Rheumatology, Hospital Bernardino Rivadavia, Buenos Aires, Argentina.
6
Division of Rheumatology and Immunology, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA. Electronic address: Wael.Jarjour@osumc.edu.

Abstract

Recent studies implicate innate immunity to systemic lupus erythematosus (SLE) pathogenesis. Toll-like receptor (TLR)8 is estrogen-regulated and binds viral ssRNA to stimulate innate immune responses, but recent work indicates that microRNA (miR)-21 within extracellular vesicles (EVs) can also trigger this receptor. Our objective was to examine TLR8 expression/activation to better understand sex-biased responses involving TLR8 in SLE. Our data identify an estrogen response element that promotes STAT1 expression and demonstrate STAT1-dependent transcriptional activation of TLR8 with estrogen stimulation. In lieu of viral ssRNA activation, we explored EV-encapsulated miR-21 as an endogenous ligand and observed induction of both TLR8 and cytokine expression in vitro. Moreover, extracellular miR detection was found predominantly within EVs. Thus, just as a cytokine or chemokine, EV-encapsulated miR-21 can act as an inflammatory signaling molecule, or miRokine, by virtue of being an endogenous ligand of TLR8. Collectively, our data elucidates a novel innate inflammatory pathway in SLE.

KEYWORDS:

Estrogen; Extracellular vesicles; Innate immunity; Systemic lupus erythematosus; Toll-like receptor (TLR)8; microRNA (miR)

PMID:
28039018
PMCID:
PMC5815376
DOI:
10.1016/j.clim.2016.12.005
[Indexed for MEDLINE]
Free PMC Article

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