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

Publication date: Available online 27 December 2016
Source:Clinical Immunology
Author(s): Nicholas A. Young, Giancarlo R. Valiente, Jeffrey M. Hampton, Lai-Chu Wu, Craig J. Burd, William L. Willis, Michael Bruss, Holly Steigelman, Maya Gotsatsenko, Stephanie A. Amici, Mary Severin, Lucila Marino Claverie, Mireia Guerau-de-Arellano, Amy Lovett-Racke, Stacy Ardoin, Wael N. Jarjour
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.

Graphical abstract

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