Macrophage Migration Inhibitory Factor Promotes Resistance To Glucocorticoid Treatment In Eae

Objective: Glucocorticoids (GCs) are used as standard treatment for acute attacks of multiple sclerosis (MS). However, GCs eventually lose efficacy and do not prevent disease progression. Macrophage migration inhibitory factor (MIF) is the only known proinflammatory cytokine induced by GCs that inhibits their anti-inflammatory effects. Therefore, we investigated whether MIF plays a role in resistance to GC treatment in experimental autoimmune encephalomyelitis (EAE), an animal model of MS.Methods: EAE was induced in wild-type (Wt) and MIF knockout (MIF2/2) mice followed by treatment with dexamethasone (Dex) before or upon disease onset. Splenocytes and brain mononuclear cells were harvested for cytokine ELISPOT assay and flow cytometry analysis.Results: Treatment of EAE with Dex was substantially more efficacious in MIF2/2 mice than Wt mice. Dex treatment decreasedMOG35-55-induced cytokine production by Wt or MIF2/2 CD41 T cells only at the onset of EAE but inhibited upregulation of T-bet during acute and chronic phases of disease, particularly in MIF2/2 mice. Furthermore, passive EAE induced by adoptive transfer of T cells showed that Dex was highly effective in ameliorating disease induced by MIF2/2 CD41 T cells but not by Wt CD41 T cells. The expression of T-bet and VLA-4 was decreased in CD41 T cells in MIF2/2 mice compared with Wt mice.Conclusions: Our data establish MIF as a key molecule in resistance of pathogenic CD41 T cells to GC treatment in EAE and as a potential target to enhance the effectiveness of steroid treatment in neuroinflammatory disorders.