The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation.
Activated microglia and macrophages (CNS macrophages) have been implicated in the secondary or "bystander" pathology (e.g. axon injury, demyelination) that accompanies traumatic or autoimmune injury to the brain and spinal cord. These cells also can provide neurotrophic support and promote axonal regeneration. Studying the divergent functional potential of CNS macrophages in trauma models is especially difficult due to the various degradative mechanisms that are initiated prior to or concomitant with microglial/macrophage activation (e.g. hemorrhage, edema, excitotoxicity, lipid peroxidation). To study the potential impact of activated CNS macrophages on the spinal cord parenchyma, we have characterized an in vivo model of non-traumatic spinal cord neuroinflammation. Specifically, focal activation of CNS macrophages was achieved using stereotaxic microinjections of zymosan. Although microinjection does not cause direct mechanical trauma, localized activation of macrophages with zymosan acts as an "inflammatory scalpel" causing tissue injury at and nearby the injection site. The present data reveal that activation of CNS macrophages in vivo can result in permanent axonal injury and demyelination. Moreover, the pathology can be graded and localized to specific white matter tracts to produce quantifiable behavioral deficits. Further development of this model will help to clarify the biological potential of microglia and macrophages and the molecular signals that control their function within the spinal cord.
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine & Public Health and School of Allied Medical Professions, Columbus 43210, USA.
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Popovich
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Guan
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McGaughy
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Fisher
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Hickey
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Basso
D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051926:Basigin; D001798:Blood Proteins; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D003714:Denervation / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008845:Microinjections; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009187:Myelitis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology; D015054:Zymosan / Q000494:pharmacology
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D008562:Membrane Glycoproteins; D051926:Basigin; D015054:Zymosan