title: Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology.
abstract: Astrocytes are key players in the pathology of multiple sclerosis and can assume beneficial and detrimental roles during lesion development. The triggers and timing of the different astroglial responses in acute lesions remain unclear. Astrocytes in acute multiple sclerosis lesions have been shown previously to contain myelin debris, although its significance has not been examined. We hypothesized that myelin phagocytosis by astrocytes is an early event during lesion formation and leads to astroglial immune responses. We examined multiple sclerosis lesions and other central nervous system pathologies with prominent myelin injury, namely, progressive multifocal leukoencephalopathy, metachromatic leukodystrophy and subacute infarct. In all conditions, we found that myelin debris was present in most astrocytes at sites of acute myelin breakdown, indicating that astroglial myelin phagocytosis is an early and prominent feature. Functionally, myelin debris was taken up by astrocytes through receptor-mediated endocytosis and resulted in astroglial NF-κB activation and secretion of chemokines. These in vitro results in rats were validated in human disease where myelin-positive hypertrophic astrocytes showed increased nuclear localization of NF-κB and elevated chemokine expression compared to myelin-negative, reactive astrocytes. Thus, our data suggest that myelin uptake is an early response of astrocytes in diseases with prominent myelin injury that results in recruitment of immune cells. This first line response of astrocytes to myelin injury may exert beneficial or detrimental effects on the lesion pathology, depending on the inflammatory context. Modulating this response might be of therapeutic relevance in multiple sclerosis and other demyelinating conditions.
authors.affiliation: Yale University, School of Medicine, Department of Neurology, 300 George St, New Haven, CT 06511, USA gerald.ponath@yale.edu.
authors.forename: Gerald
authors.initials: G
authors.lastname: Ponath
authors.affiliation: Yale University, School of Medicine, Department of Neurology, 300 George St, New Haven, CT 06511, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Ramanan
authors.affiliation: Yale University, School of Medicine, Department of Neurology, 300 George St, New Haven, CT 06511, USA.
authors.forename: Mayyan
authors.initials: M
authors.lastname: Mubarak
authors.affiliation: Yale University, School of Medicine, Department of Neurology, 300 George St, New Haven, CT 06511, USA.
authors.forename: William
authors.initials: W
authors.lastname: Housley
authors.affiliation: Yale University, School of Medicine, Department of Ophthalmology and Visual Science, 300 George St, New Haven, CT 06511, USA.
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Lee
authors.affiliation: The Ohio State University College of Medicine, Department of Neuroscience, 670 Biomedical Research Tower, Columbus, OH, 43210, USA.
authors.forename: F Rezan
authors.initials: FR
authors.lastname: Sahinkaya
authors.affiliation: Yale University, School of Medicine, Department of Pathology, 310 Cedar Street New Haven, CT 06520-8023, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vortmeyer
authors.affiliation: Albert Einstein College of Medicine, Department of Pathology (Neuropathology), 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.affiliation: Yale University, School of Medicine, Department of Neurology, 300 George St, New Haven, CT 06511, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pitt
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002675:Child, Preschool; D003469:Culture; D016207:Cytokines / Q000378:metabolism; D020278:Demyelinating Autoimmune Diseases, CNS / Q000473:pathology*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology*; D010587:Phagocytosis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D016207:Cytokines; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D016212:Transforming Growth Factor beta
keywords: T-lymphocytes; astrocyte; demyelination; multiple sclerosis and neuroinflammation; neuroimmunology