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.

The Therapeutic Potential of Rho Kinase Inhibitor Fasudil Derivative FaD-1 in Experimental Autoimmune Encephalomyelitis

“…M2-conditioned media encouraged axon growth (Kigerl et al 2009) and M2 microglia/ macrophages induced oligodendrocyte differentiation during CNS remyelination (Miron et al 2013). A single administration of M2 microglia attenuated the severity of EAE, accompanied by reduced inflammatory responses and less demyelination (Zhang et al 2014). Our data reveal that FaD-1 may work in the early disease phase of EAE by suppressing the microglia activation polarized to M1, leading to the suppression of the pathogenesis of disease.…”

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

“…In vitro studies demonstrate that M2 cells have the ability to induce CD4 + Tregs with a strong suppressive anti-inflammatory function [115,116]. Similarly, CD4+ T cells cultured with M1 macrophages can produce a proinflammatory interferon (IFN)-γ response [117].…”

“…Similar to Tregs, passive transfer may be an option. Transfer or M2 microglia/macrophages has been shown to be an effective treatment in experimental autoimmune encephalitis [116]. Already in clinical trial, NP001, a novel immunomodulator of proinflmmatory monocyte/macrophages, appeared to suppress neuroinflammation and slow progression in ALS, but these results await a larger confirmatory study [163].…”

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

“…The etiology of this heterogeneous disease has been related to immunologic, environmental, and genetic factors, but its precise cause is still unknown (Milo & Kahana 2010). The pathogenesis of the disease is accompanied by activation and infiltration of mononuclear cells predominantly antigen-specific CD4 þ and CD8 þ T-cells and Bcells in the CNS (Mosayebi et al 2010;Zhang et al 2014).…”