Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Authors

Claudia Cantoni, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.Follow
Francesca Cignarella, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Laura Ghezzi, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Bob Mikesell, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Bryan Bollman, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Melissa M. Berrien-Elliott, Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Aaron R. Ireland, Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Todd A. Fehniger, Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Gregory F. Wu, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Laura Piccio, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA. picciol@neuro.wustl.edu.

Document Type

Article

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.

Keywords

MiR-223, MicroRNA, Multiple sclerosis, Myeloid-derived suppressor cells

Medical Subject Headings

Animals; Arginase (metabolism); Brain (metabolism, pathology); Cell Count; Encephalomyelitis, Autoimmune, Experimental (metabolism, pathology); Humans; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs (genetics, metabolism); Multiple Sclerosis, Relapsing-Remitting (metabolism, pathology); Myeloid-Derived Suppressor Cells (metabolism, pathology); STAT3 Transcription Factor (metabolism); Spinal Cord (metabolism, pathology); Spleen (metabolism, pathology); T-Lymphocytes (metabolism, pathology)

Publication Date

1-1-2017

Publication Title

Acta neuropathologica

E-ISSN

1432-0533

Volume

133

Issue

1

First Page

61

Last Page

77

PubMed ID

27704281

Digital Object Identifier (DOI)

10.1007/s00401-016-1621-6

Recommended Citation

Cantoni, Claudia; Cignarella, Francesca; Ghezzi, Laura; Mikesell, Bob; Bollman, Bryan; Berrien-Elliott, Melissa M.; Ireland, Aaron R.; Fehniger, Todd A.; Wu, Gregory F.; and Piccio, Laura, "Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis" (2017). Translational Neuroscience. 2338.
https://scholar.barrowneuro.org/neurobiology/2338