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.
- 4.Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S et al (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150. doi: 10.1038/ncomms12150 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.De Santis G, Ferracin M, Biondani A, Caniatti L, Rosaria Tola M, Castellazzi M, Zagatti B, Battistini L, Borsellino G, Fainardi E et al (2010) Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol 226:165–171. doi: 10.1016/j.jneuroim.2010.06.009 CrossRefPubMedGoogle Scholar
- 7.Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, Diverio D, Ammatuna E, Cimino G, Lo-Coco F et al (2007) Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12:457–466. doi: 10.1016/j.ccr.2007.09.020 CrossRefPubMedGoogle Scholar
- 9.Fenoglio C, Ridolfi E, Cantoni C, De Riz M, Bonsi R, Serpente M, Villa C, Pietroboni AM, Naismith RT, Alvarez E et al (2013) Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis. Mult Scler 19:1938–1942. doi: 10.1177/1352458513485654 CrossRefPubMedGoogle Scholar
- 13.Gimenez MA, Sim J, Archambault AS, Klein RS, Russell JH (2006) A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. Am J Pathol 168:1200–1209. doi: 10.2353/ajpath.2006.050332 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Guerau-de-Arellano M, Liu Y, Meisen WH, Pitt D, Racke MK, Lovett-Racke AE (2015) Analysis of miRNA in normal appearing white matter to identify altered CNS pathways in multiple sclerosis. J Autoimmune Disord 1:1–8Google Scholar
- 18.Ioannou M, Alissafi T, Lazaridis I, Deraos G, Matsoukas J, Gravanis A, Mastorodemos V, Plaitakis A, Sharpe A, Boumpas D et al (2012) Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. J Immunol 188:1136–1146. doi: 10.4049/jimmunol.1101816 CrossRefPubMedGoogle Scholar
- 23.Keller A, Leidinger P, Lange J, Borries A, Schroers H, Scheffler M, Lenhof HP, Ruprecht K, Meese E (2009) Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One 4:e7440. doi: 10.1371/journal.pone.0007440 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Li T, Morgan MJ, Choksi S, Zhang Y, Kim YS, Liu ZG (2010) MicroRNAs modulate the noncanonical transcription factor NF-kappaB pathway by regulating expression of the kinase IKKalpha during macrophage differentiation. Nat Immunol 11:799–805. doi: 10.1038/ni.1918 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Moline-Velazquez V, Cuervo H, Vila-Del Sol V, Ortega MC, Clemente D, de Castro F (2011) Myeloid-derived suppressor cells limit the inflammation by promoting T lymphocyte apoptosis in the spinal cord of a murine model of multiple sclerosis. Brain Pathol 21:678–691. doi: 10.1111/j.1750-3639.2011.00495.x CrossRefPubMedGoogle Scholar
- 36.Parekh VV, Wu L, Olivares-Villagomez D, Wilson KT, Van Kaer L (2013) Activated invariant NKT cells control central nervous system autoimmunity in a mechanism that involves myeloid-derived suppressor cells. J Immunol 190:1948–1960. doi: 10.4049/jimmunol.1201718 CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Piccio L, Cantoni C, Henderson JG, Hawiger D, Ramsbottom M, Mikesell R, Ryu J, Hsieh CS, Cremasco V, Haynes W et al (2013) Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis. Eur J Immunol 43:2089–2100. doi: 10.1002/eji.201242836 CrossRefPubMedPubMedCentralGoogle Scholar