title: Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu.
abstract: Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance to self-Ags and activation of autoreactive T cells. Regulatory T (Treg) cells play a critical role in controlling the activation of autoreactive T cells. In this study, we investigated mechanisms of potential Treg cell defects in systemic lupus erythematosus using MRL-Fas(lpr/lpr) (MRL/lpr) and MRL-Fas(+/+) mouse models. We found a significant increase in CD4(+)CD25(+)Foxp3(+) Treg cells, albeit with an altered phenotype (CD62L(-)CD69(+)) and with a reduced suppressive capacity, in the lymphoid organs of MRL strains compared with non-autoimmune C3H/HeOuj mice. A search for mechanisms underlying the altered Treg cell phenotype in MRL/lpr mice led us to find a profound reduction in Dicer expression and an altered microRNA (miRNA, miR) profile in MRL/lpr Treg cells. Despite having a reduced level of Dicer, MRL/lpr Treg cells exhibited a significant overexpression of several miRNAs, including let-7a, let-7f, miR-16, miR-23a, miR-23b, miR-27a, and miR-155. Using computational approaches, we identified one of the upregulated miRNAs, miR-155, that can target CD62L and may thus confer the altered Treg cell phenotype in MRL/lpr mice. In fact, the induced overexpression of miR-155 in otherwise normal (C3H/HeOuj) Treg cells reduced their CD62L expression, which mimics the altered Treg cell phenotype in MRL/lpr mice. These data suggest a role of Dicer and miR-155 in regulating Treg cell phenotype. Furthermore, simultaneous appearance of Dicer insufficiency and miR-155 overexpression in diseased mice suggests a Dicer-independent alternative mechanism of miRNA regulation under inflammatory conditions.
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Anagha A
authors.initials: AA
authors.lastname: Divekar
authors.forename: Shweta
authors.initials: S
authors.lastname: Dubey
authors.forename: Pallavi R
authors.initials: PR
authors.lastname: Gangalum
authors.forename: Ram Raj
authors.initials: RR
authors.lastname: Singh
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D004722:Endoribonucleases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D043244:Ribonuclease III; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases