Deletion of microRNA-183-96-182 Cluster in Lymphocytes Suppresses Anti-DsDNA Autoantibody Production and IgG Deposition in the Kidneys in C57BL/6-Fas(lpr/lpr) Mice

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dc.contributor.authorWang, Zhuangen
dc.contributor.authorHeid, Bettinaen
dc.contributor.authorLu, Ranen
dc.contributor.authorSachdeva, Mohiten
dc.contributor.authorEdwards, Michael R.en
dc.contributor.authorRen, JingJingen
dc.contributor.authorCecere, Thomas E.en
dc.contributor.authorKhan, Deenaen
dc.contributor.authorJeboda, Taschuaen
dc.contributor.authorKirsch, David G.en
dc.contributor.authorReilly, Christopher M.en
dc.contributor.authorDai, Rujuanen
dc.contributor.authorAhmed, S. Ansaren
dc.date.accessioned2022-11-02T17:37:56Zen
dc.date.available2022-11-02T17:37:56Zen
dc.date.issued2022-07-07en
dc.description.abstractDysregulated miRNAs have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Our previous study reported a substantial increase in three miRNAs located at the miR-183-96-182 cluster (miR-183C) in several autoimmune lupus-prone mice, including MRL/lpr and C57BL/6-lpr (B6/lpr). This study reports that in vitro inhibition of miR-182 alone or miR-183C by specific antagomirs in activated splenocytes from autoimmune-prone MRL/lpr and control MRL mice significantly reduced lupus-related inflammatory cytokines, interferon-gamma (IFN gamma), and IL-6 production. To further characterize the role of miR-182 and miR-183C cluster in vivo in lupus-like disease and lymphocyte phenotypes, we used hCD2-iCre to generate B6/lpr mice with conditional deletion of miR-182 or miR-183C in CD2(+) lymphocytes (miR-182(-/-)B6/lpr and miR-183C(-/-)B6/lpr). The miR-182(-/-)B6/lpr and miR-183C(-/-)B6/lpr mice had significantly reduced deposition of IgG immunocomplexes in the kidney when compared to their respective littermate controls, although there appeared to be no remarkable changes in renal pathology. Importantly, we observed a significant reduction of serum anti-dsDNA autoantibodies in miR-183C(-/-)B6/lpr mice after reaching 24 weeks-of age compared to age-matched miR-183C(fl/fl)B6/lpr controls. In vitro activated splenocytes from miR-182(-/-)B6/lpr mice and miR-183C(-/-)B6/lpr mice showed reduced ability to produce lupus-associated IFN gamma. Forkhead box O1(Foxo1), a previously validated miR-183C miRNAs target, was increased in the splenic CD4(+) cells of miR-182(-/-)B6/lpr and miR-183C(-/-)B6/lpr mice. Furthermore, in vitro inhibition of Foxo1 with siRNA in splenocytes from miR-182(-/-)B6/lpr and miR-183C(-/-)B6/lpr mice significantly increased IFN gamma expression following anti-CD3/CD28 stimulation, suggesting that miR-182 and miR-183C miRNAs regulate the inflammatory IFN gamma in splenocytes via targeting Foxo1. The deletion of either miR-182 alone or the whole miR-183C cluster, however, had no marked effect on the composition of T and B cell subsets in the spleens of B6/lpr mice. There were similar percentages of CD4(+), CD8(+), CD19(+), as well as Tregs, follicular helper T (T-FH), germinal center B (GCB), and plasma cells in the miR-183C(-/-)B6/lpr and miR-182(-/-)B6/lpr mice and their respective littermate controls, miR-183C(fl/fl)B6/lpr and miR-182(fl/fl)B6/lpr mice. Together, our data demonstrate a role of miR-183C in the regulation of anti-dsDNA autoantibody production in vivo in B6/lpr mice and the induction of IFN gamma in in vitro activated splenocytes from B6/lpr mice.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fgene.2022.840060en
dc.identifier.eissn1664-8021en
dc.identifier.other840060en
dc.identifier.pmid35873462en
dc.identifier.urihttp://hdl.handle.net/10919/112365en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectepigeneticsen
dc.subjectmiR-183-96-182 clusteren
dc.subjectautoantibodyen
dc.subjectinflammatory cytokineen
dc.subjectsystemic lupus erythematosusen
dc.subjectmurine modelen
dc.titleDeletion of microRNA-183-96-182 Cluster in Lymphocytes Suppresses Anti-DsDNA Autoantibody Production and IgG Deposition in the Kidneys in C57BL/6-Fas(lpr/lpr) Miceen
dc.title.serialFrontiers in Geneticsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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