title: Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis.
abstract: Myeloid-derived cells play important modulatory and effector roles in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, composed of monocytic (MO) and polymorphonuclear (PMN) fractions, which can suppress T cell activities in EAE. Their role in MS remains poorly characterized. We found decreased numbers of circulating MDSCs, driven by lower frequencies of the MO-MDSCs, and higher MDSC expression of microRNA miR-223 in MS versus healthy subjects. To gain mechanistic insights, we interrogated the EAE model. MiR-223 knock out (miR-223-/-) mice developed less severe EAE with increased MDSC numbers in the spleen and spinal cord compared to littermate controls. MiR-223-/-MO-MDSCs suppressed T cell proliferation and cytokine production in vitro and EAE in vivo more than wild-type MO-MDSCs. They also displayed an increased expression of critical mediators of MDSC suppressive function, Arginase-1(Arg1), and the signal transducer and activator of transcription 3 (Stat3), which herein, we demonstrate being an miR-223 target gene. Consistently, MDSCs from MS patients displayed decreased STAT3 and ARG1 expression compared with healthy controls, suggesting that circulating MDSCs in MS are not only reduced in numbers but also less suppressive. These results support a critical role for miR-223 in modulating MDSC biology in EAE and in MS and suggest potential novel therapeutic applications.
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cantoni
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cignarella
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.|Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ghezzi
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
authors.forename: Bob
authors.initials: B
authors.lastname: Mikesell
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Bollman
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Berrien-Elliott
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Ireland
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Wu
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA. picciol@neuro.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. picciol@neuro.wustl.edu.
authors.forename: Laura
authors.identifier: 0000-0002-8760-109X
authors.initials: L
authors.lastname: Piccio
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000378:metabolism* / Q000473:pathology; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D001119:Arginase; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C525067:MIR223, human; C544877:MIRN223 microRNA, mouse; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C574619:ARG1 protein, human; C544448:Arg1 protein, mouse
keywords: MiR-223; MicroRNA; Multiple sclerosis; Myeloid-derived suppressor cells