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Mesenchymal Stromal Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Inhibiting CD4 Th17 T Cells in a CC Chemokine Ligand 2-Dependent Manner¹

Moutih Rafei^*, Philippe M. Campeau^*, Adriana Aguilar-Mahecha^*, Marguerite Buchanan^*, Patrick Williams^*, Elena Birman^*, Shala Yuan^*, Yoon Kow Young^*, Marie-Noëlle Boivin^*, Kathy Forner^*, Mark Basik and Jacques Galipeau^2,*

^* Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; and Departments of Oncology and Surgery, McGill University, Montreal, Quebec, Canada

The administration of ex vivo culture-expanded mesenchymal stromal cells (MSCs) has been shown to reverse symptomatic neuroinflammation observed in experimental autoimmune encephalomyelitis (EAE). The mechanism by which this therapeutic effect occurs remains unknown. In an effort to decipher MSC mode of action, we found that MSC conditioned medium inhibits EAE-derived CD4 T cell activation by suppressing STAT3 phosphorylation via MSC-derived CCL2. Further analysis demonstrates that the effect is dependent on MSC-driven matrix metalloproteinase proteolytic processing of CCL2 to an antagonistic derivative. We also show that antagonistic CCL2 suppresses phosphorylation of AKT and leads to a reciprocal increased phosphorylation of ERK associated with an up-regulation of B7.H1 in CD4 T cells derived from EAE mice. CD4 T cell infiltration of the spinal cord of MSC-treated group was robustly decreased along with reduced plasma levels of IL-17 and TNF- levels and in vitro from restimulated splenocytes. The key role of MSC-derived CCL2 was confirmed by the observed loss of function of CCL2^–/– MSCs in EAE mice. In summary, this is the first report of MSCs modulating EAE biology via the paracrine conversion of CCL2 from agonist to antagonist of CD4 Th17 cell function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Canadian Institute of Health Research Grant MOP-15017 (to J.G.). M.R. is a recipient of a Fonds de Recherches en Santé du Québec (FRSQ) Scholarship, and J.G. is a FRSQ chercheur-boursier sénior.

² Address correspondence and reprint requests to Dr. Jacques Galipeau, Division of Hematology/Oncology, Jewish General Hospital, McGill University, Montreal, Canada 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada, H3T 1E2. E-mail address: jacques.galipeau{at}mcgill.ca

³ Abbreviations used in this paper: MS, multiple sclerosis; CM, conditioned medium; EAE, experimental autoimmune encephalomyelitis; MHCI, MHC class I; MHCII, MHC class II; MMP, matrix metalloproteinase; pAKT, phospho-AKT; PD-1, programmed death-1; pERK, phospho-ERK; pSTAT3, STAT3 phosphorylation; SELDI-TOF, surface-enhanced laser desorption ionization-time of flight; WB, Western blot; WT, wild type.

⁴ The online version of this article contains supplemental material.