Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis
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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.
KeywordsMicroRNA MiR-223 Multiple sclerosis Myeloid-derived suppressor cells
Myeloid-derived suppressor cells
Experimental autoimmune encephalomyelitis
Signal transducer and activator of transcription 3
We thank Anne H. Cross, MD for careful reading of the manuscript; Julia Sim and Angela Archambault, PhD for technical assistance and advices; Erin Longbrake, MD PhD for helping with patient enrollment in the study; all MS patients and healthy controls that donated blood for this project as well as the study coordinators that drew the blood: Samantha Lancia, Susan Fox, and Bridgette Clay. LP is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society (NMSS, JF 2144A2/1) and supported by Fondazione Italiana Sclerosi Multipla (FISM; 2014/R/15). GFW was supported by R01NS083678. LP and GFW were funded by the Dana Foundation “Program in the Neuroimmunology and Brain Infections and Cancer”. CC was supported during the course of this study by a FISM fellowship (2012/B/1) and subsequently by a NMSS fellowship (FG 2010-A1/2). TAF was supported by R01AI102924. Patients were seen for this study in the Neuroclinical Research Unit (NCRU) supported by the National Institute of Health (CO6 RR020092) and Washington University Insitute of Clinical and Translational Sciences-Brain Behavioral and Performance Unit (TR000448).
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interests.
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