Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination.
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.
Centre for Brain Research, Medical University of Vienna, Vienna, Austria.
Rakhi
R
Sharma
Marie-Therese
MT
Fischer
Jan
J
Bauer
Paul A
PA
Felts
Kenneth J
KJ
Smith
Tatsuro
T
Misu
Kazuo
K
Fujihara
Monika
M
Bradl
Hans
H
Lassmann
D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D018920:Coculture Techniques / Q000379:methods; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
C496030:AQP4 protein, human; D051401:Aquaporin 4; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011134:Polysaccharides