title: Adoptive transfer of cytokine-induced immunomodulatory adult microglia attenuates experimental autoimmune encephalomyelitis in DBA/1 mice.
abstract: Microglia are resident antigen-presenting cells in the central nervous system (CNS) that either suppress or promote disease depending on their activation phenotype and the microenvironment. Multiple sclerosis (MS) is a chronic inflammatory disease causing demyelination and nerve loss in the CNS, and experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate pathogenic mechanisms and therapeutic effects. We isolated and cultured microglia from adult mouse brains and exposed them to specific combinations of stimulatory molecules and cytokines, the combination of IL-4, IL-10, and TGF-β yielding the optimal regime for induction of an immunosuppressive phenotype (M2). M2 microglia were characterized by decreased expression or production of CD86, PD-L1, nitric oxide, and IL-6, increased expression of PD-L2, and having a potent capacity to retain their phenotype on secondary proinflammatory stimulation. M2 microglia induced regulatory T cells, suppressed T-cell proliferation, and downmodulated M1-associated receptor expression in M1 macrophages. Myelin oligodendrocyte glycoprotein (MOG)-induced EAE was induced in DBA/1 mice and at different time points (0, 5, 12, or 15 days postimmunization) 3 × 105 M2 microglia were transferred intranasally. A single transfer of M2 microglia attenuated the severity of established EAE, which was particularly obvious when the cells were injected at 15 days postimmunization. M2 microglia-treated mice had reduced inflammatory responses and less demyelination in the CNS. Our findings demonstrate that adult M2 microglia therapy represents a novel intervention that alleviated established EAE and that this therapeutic principle may have relevance for treatment of MS patients.
authors.forename: Xing-Mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Harald
authors.initials: H
authors.lastname: Lund
authors.forename: Sohel
authors.initials: S
authors.lastname: Mia
authors.forename: Roham
authors.initials: R
authors.lastname: Parsa
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy*; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*
chemical_list: D016207:Cytokines