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A small-molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease
Aaron P Kithcart1, Gina M Cox, Thais Sielecki
1Department of Molecular Virology, Immunology, and Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA.
Abstract:
Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) characterized by demyelination and axon loss. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be elevated in the cerebrospinal fluid of patients during relapses. The purpose of this study was to evaluate a new small-molecule inhibitor of MIF and its ability to reduce the severity of an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We utilized 2 structurally related isoxazolines, which show in vitro inhibition of MIF tautomerase activity. We found that administration of an inhibitor of MIF to mice with established EAE immediately reduced the severity of clinical signs and expanded a population of regulatory T lymphocytes. We also noted that the inhibitor reduced relapses of disease in a relapsing/remitting model of EAE. An analysis of leukocyte migration into the brain revealed that administration of inhibitor reduced entry of these cells. No effects on inflammatory cytokine production or T-cell activation in the periphery were noted. From these studies, we conclude that a small-molecule inhibitor of MIF reduces the severity of EAE and prevents access of immune cells into the CNS, which could be of therapeutic relevance to MS.
Insights
A novel small-molecule inhibitor targeting macrophage migration inhibitory factor (MIF) effectively reduced multiple sclerosis (MS) disease severity in a mouse model. This therapeutic approach limited immune cell entry into the central nervous system (CNS).
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a chronic central nervous system (CNS) disease causing demyelination and axon loss.
- Elevated levels of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) are observed during MS relapses.
Purpose of the Study:
- To evaluate a new small-molecule inhibitor of MIF for its efficacy in reducing the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of MS.
Main Methods:
- Utilized two structurally related isoxazolines with in vitro MIF tautomerase inhibitory activity.
- Administered MIF inhibitor to mice with established EAE and a relapsing/remitting EAE model.
- Analyzed leukocyte migration into the brain and peripheral T-cell activation/cytokine production.
Main Results:
- MIF inhibitor administration immediately reduced clinical signs of EAE and expanded regulatory T lymphocytes.
- The inhibitor decreased disease relapses in a relapsing/remitting EAE model.
- Reduced leukocyte infiltration into the CNS without affecting peripheral inflammatory cytokine production or T-cell activation.
Conclusions:
- Small-molecule MIF inhibition effectively reduces EAE severity and prevents immune cell entry into the CNS.
- This therapeutic strategy holds potential relevance for treating multiple sclerosis.
