MicroRNA-302d targets IRF9 to regulate the IFN-induced gene expression in SLE.
Systemic lupus erythematosus (SLE) is a complex disease targeting multiple organs as a result of overactivation of the type I interferon (IFN) system, a feature currently being targeted by multiple biologic therapies against IFN-α. We have identified an estrogen-regulated microRNA, miR-302d, whose expression is decreased in SLE patient monocytes and identify its target as interferon regulatory factor (IRF)-9, a critical component of the transcriptional complex that regulates expression of interferon-stimulated genes (ISGs). In keeping with the reduced expression of miR-302d in SLE patient monocytes, IRF9 levels were increased, as was expression of a number of ISGs including MX1 and OAS1. In vivo evaluation revealed that miR-302d protects against pristane-induced inflammation in mice by targeting IRF9 and hence ISG expression. Importantly, patients with enhanced disease activity have markedly reduced expression of miR-302d and enhanced IRF9 and ISG expression, with miR-302d negatively correlating with IFN score. Together these findings identify miR-302d as a key regulator of type I IFN driven gene expression via its ability to target IRF9 and regulate ISG expression, underscoring the importance of non-coding RNA in regulating the IFN pathway in SLE.
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Siobhán
S
Smith
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Thilini
T
Fernando
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Pei Wen
PW
Wu
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Jane
J
Seo
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Joan
J
Ní Gabhann
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Olga
O
Piskareva
Department of Rheumatology, Beaumont Hospital, Dublin 9, Ireland.
Eoghan
E
McCarthy
Department of Rheumatology, Beaumont Hospital, Dublin 9, Ireland.
Donough
D
Howard
Department of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland.
Paul
P
O'Connell
Department of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland.
Richard
R
Conway
Department of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland.
Phil
P
Gallagher
Department of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland.
Eamonn
E
Molloy
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Raymond L
RL
Stallings
Department of Biomedical Sciences, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Grainne
G
Kearns
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Lindsy
L
Forbess
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Mariko
M
Ishimori
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Swamy
S
Venuturupalli
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Daniel
D
Wallace
Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Michael
M
Weisman
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, CA 90048, USA. Electronic address: Caroline.Jefferies@cshs.org.
Caroline A
CA
Jefferies
D000818:Animals; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004967:Estrogens / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
D004967:Estrogens; C494227:IRF9 protein, human; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C532169:MIRN302A microRNA, human; D035683:MicroRNAs
IFN signalling; IFN-stimulated genes; MicroRNA; SLE