Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology

Gerald Ponath, Sriram Ramanan, Mayyan Mubarak, William Housley, Seunghoon Lee, F. Rezan Sahinkaya, Alexander Vortmeyer, Cedric S. Raine, David Pitt

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)399-413
Number of pages15
JournalBrain
Volume140
Issue number2
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Myelin Sheath
Phagocytosis
Astrocytes
Pathology
Multiple Sclerosis
Chemokines
Wounds and Injuries
Metachromatic Leukodystrophy
Progressive Multifocal Leukoencephalopathy
Endocytosis
Central Nervous System

Keywords

  • Astrocyte
  • Demyelination
  • Multiple sclerosis and neuroinflammation
  • Neuroimmunology
  • T-lymphocytes

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Ponath, G., Ramanan, S., Mubarak, M., Housley, W., Lee, S., Sahinkaya, F. R., ... Pitt, D. (2017). Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. Brain, 140(2), 399-413. https://doi.org/10.1093/brain/aww298

Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. / Ponath, Gerald; Ramanan, Sriram; Mubarak, Mayyan; Housley, William; Lee, Seunghoon; Sahinkaya, F. Rezan; Vortmeyer, Alexander; Raine, Cedric S.; Pitt, David.

In: Brain, Vol. 140, No. 2, 01.01.2017, p. 399-413.

Research output: Contribution to journalArticle

Ponath, G, Ramanan, S, Mubarak, M, Housley, W, Lee, S, Sahinkaya, FR, Vortmeyer, A, Raine, CS & Pitt, D 2017, 'Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology', Brain, vol. 140, no. 2, pp. 399-413. https://doi.org/10.1093/brain/aww298
Ponath G, Ramanan S, Mubarak M, Housley W, Lee S, Sahinkaya FR et al. Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. Brain. 2017 Jan 1;140(2):399-413. https://doi.org/10.1093/brain/aww298
Ponath, Gerald ; Ramanan, Sriram ; Mubarak, Mayyan ; Housley, William ; Lee, Seunghoon ; Sahinkaya, F. Rezan ; Vortmeyer, Alexander ; Raine, Cedric S. ; Pitt, David. / Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. In: Brain. 2017 ; Vol. 140, No. 2. pp. 399-413.
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