title: Microglial inhibitory factor (MIF/TKP) mitigates secondary damage following spinal cord injury.
abstract: Spinal cord injury (SCI) induces an immune response during which microglia, the resident immunocompetent cells of the central nervous system, become activated and migrate to the site of damage. Depending on their state of activation, microglia secrete neurotoxic or neurotrophic factors that influence the surrounding environment and have a detrimental or restorative effect following SCI, including causing or protecting bystander damage to nearby undamaged tissue. Subsequent infiltration of macrophages contributes to the SCI outcome. We show here that suppressing microglia/macrophage activation using the tripeptide macrophage/microglia inhibitory factor (MIF/TKP) reduced secondary injury around the lesion epicenter in the murine dorsal hemisection model of SCI; it decreased the hypertrophic change of astrocytes and caused an increase in the number of axons present within the lesion epicenter. Moreover, timely inhibition of microglial/macrophage activation prevented demyelination and axonal dieback by modulating oligodendrocyte survival and oligodendrocyte precursor maturation. Microglia/macrophages located within or proximal to the lesion produced neurotoxic factors, such as tumor necrosis factor alpha (TNF-α). These results suggest that microglia/macrophages within the epicenter at early time points post injury are neurotoxic, contributing to demyelination and axonal degeneration and that MIF/TKP could be used in combination with other therapies to promote functional recovery.
authors.affiliation: Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, NY 11794‐8651, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Emmetsberger
authors.forename: Stella E
authors.initials: SE
authors.lastname: Tsirka
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D000071183:Autophagy-Related Proteins; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002772:Cholera Toxin; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D004676:Myelin Basic Protein / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000627:therapeutic use*; D010446:Peptide Fragments; D011509:Proteoglycans / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology*; D013997:Time Factors; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D000071183:Autophagy-Related Proteins; D001973:Bromodeoxyuridine; D002135:Calcium-Binding Proteins; D002772:Cholera Toxin; D011508:Chondroitin Sulfate Proteoglycans; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D004676:Myelin Basic Protein; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C491049:Aif1 protein, mouse; C428743:Rb1cc1 protein, mouse; C084765:cholera toxin B subunit (50-75); C045468:threonyl-lysyl-proline