title: Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus.
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.
authors.affiliation: 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.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Young
authors.affiliation: 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.
authors.forename: Giancarlo R
authors.initials: GR
authors.lastname: Valiente
authors.affiliation: 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.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Hampton
authors.affiliation: 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.
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Department of Molecular Genetics, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Burd
authors.affiliation: 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.
authors.forename: William L
authors.initials: WL
authors.lastname: Willis
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Bruss
authors.affiliation: 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.
authors.forename: Holly
authors.initials: H
authors.lastname: Steigelman
authors.affiliation: 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.
authors.forename: Maya
authors.initials: M
authors.lastname: Gotsatsenko
authors.affiliation: 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.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Amici
authors.affiliation: Department of Microbial Infection and Immunity, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Severin
authors.affiliation: Department of Rheumatology, Hospital Bernardino Rivadavia, Buenos Aires, Argentina.
authors.forename: Lucila Marino
authors.initials: LM
authors.lastname: Claverie
authors.affiliation: 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.
authors.forename: Mireia
authors.initials: M
authors.lastname: Guerau-de-Arellano
authors.affiliation: Department of Microbial Infection and Immunity, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Lovett-Racke
authors.affiliation: 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.
authors.forename: Stacy
authors.initials: S
authors.lastname: Ardoin
authors.affiliation: 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.
authors.forename: Wael N
authors.initials: WN
authors.lastname: Jarjour
mesh_terms: D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism*; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D018925:Chemokines; D004967:Estrogens; D008024:Ligands; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8
keywords: Estrogen; Extracellular vesicles; Innate immunity; Systemic lupus erythematosus; Toll-like receptor (TLR)8; microRNA (miR)