Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammation

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Title: Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammation
Creators: Kithcart, Aaron
Advisor: Whitacre, Carol
Issue Date: 2009-04
Abstract: Multiple sclerosis (MS) is a demyelinating neurological disease affecting more than 400,000 Americans, causing progressive motor and sensory loss. MS is typically diagnosed during the second and third decades of life and thus is the primary cause of non-traumatic disability in the United States. The pathology of MS involves activation of autoreactive lymphocytes and their migration across the blood-brain barrier (BBB) into the central nervous system (CNS), including both the brain and spinal cord. It has been previously reported that MS patients have a higher level of the ubiquitously expressed, proinflammatory molecule MIF. We have shown that mice lacking MIF have fewer leukocytes in the CNS following induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. We therefore hypothesized that MIF was a critical mediator of leukocyte trafficking. The purpose of this study was to determine the biological source of MIF and whether an inhibitor of MIF could reduce trafficking. We found using a combination of adoptive transfer and bone marrow chimera studies that mice expressing MIF from myeloid cells had significantly more severe disease than MIF KO mice or mice expressing MIF only in non-myeloid cells. Monocytes and microglia are derived from myeloid cells and thus we believe are the critical sources of MIF. Indeed, using immunohistochemistry, we found more infiltrates in the CNS of mice when myeloid cells expressed MIF. We followed up this study by utilizing a small molecule inhibitor of MIF to evaluate whether disruption of MIF activity could inhibit lymphocyte migration. Mice had reduced severity of EAE following inhibitor administration and reduced migration of leukocytes into the CNS. Other groups have shown that blocking MIF reduces expression of adhesion molecules on the BBB. Our data suggests that during inflammatory disease, MIF from myeloid cells is critical for leukocyte migration and an inhibitor of MIF reduces migration and subsequent clinical disease. This drug could be a potential new therapeutic option for the millions of patients suffering from multiple sclerosis worldwide.
Embargo: No embargo
Series/Report no.: 2009 Edward F. Hayes Graduate Research Forum. 23rd
Keywords: Macrophage migration inhibitory factor
Multiple sclerosis
Experimental autoimmune enchephalomyelitis
Blood-brain barrier
Description: Professional Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
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