Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination

Rakhi Sharma, Marie-Therese Fischer, Jan Bauer, Paul A. Felts, Kenneth J. Smith, Tatsuro Misu, Kazuo Fujihara, Monika Bradl, Hans Lassmann

    Research output: Contribution to journalArticle

    115 Citations (Scopus)

    Abstract

    Primary loss and dysfunction of astrocytes may trigger demyelination, as seen in neuromyelitis optica, an inflammatory disease of the central nervous system. In most patients affected by this disease, injury to astrocytes is initiated by the action of autoantibodies targeting aquaporin 4 (AQP-4), a water channel on astrocytes. We show here that damage of astrocytes and subsequent demyelination can also occur in the absence of autoantibody-mediated mechanisms. Following injection of lipopolysaccharide into the white matter initial microglia activation is followed by a functional disturbance of astrocytes, mainly reflected by retraction of astrocytic foot processes at the glia limitans and loss of AQP-4 and connexins, which are involved in the formation of gap junctions between astrocytes and oligodendrocytes. Demyelination and oligodendrocyte degeneration in this model follows astrocyte pathology. Similar structural abnormalities were also seen in a subset of active lesions in multiple sclerosis. Our studies suggest that astrocyte injury may be an important early step in the cascade of lesion formation in brain inflammation.

    Original languageEnglish
    Pages (from-to)223-236
    Number of pages14
    JournalActa Neuropathologica
    Volume120
    Issue number2
    DOIs
    Publication statusPublished - Aug 2010

    Keywords

    • Brain inflammation
    • Multiple sclerosis
    • Astrocytes
    • Demyelination
    • Neuromyelitis optica
    • MYELIN OLIGODENDROCYTE GLYCOPROTEIN
    • MULTIPLE-SCLEROSIS
    • NEUROMYELITIS-OPTICA
    • GAP-JUNCTIONS
    • AUTOIMMUNE ENCEPHALOMYELITIS
    • REACTIVE ASTROCYTES
    • TRANSGENIC MICE
    • WATER CHANNEL
    • AQUAPORIN-4
    • ANTIBODIES

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