TNF-alpha transgenic and knockout models of CNS inflammation and degeneration.
Tumour necrosis factor-alpha (TNF-alpha) plays a central role in inflammatory events including those taking place in the central nervous system (CNS), and has been implicated as a key pathogenic mediator in several human inflammatory, infectious and autoimmune CNS disorders. Using transgenic and gene knockout mice we have investigated the role of deregulated TNF-alpha production in the CNS. We show that the overexpression of wild-type murine or human TNF-alpha transgenes by resident CNS astrocytes or neurons in sufficient to trigger a neurological disorder characterised by ataxia, seizures and paresis, with histopathological features of chronic CNS inflammation and white matter degeneration. Furthermore, we show that transmembrane human TNF-alpha is sufficient to trigger CNS inflammation and degeneration when overexpressed by astrocytes but not by neurons, indicating that target cells mediating the neuroinflammatory activities of TNF-alpha localise in the vicinity of astrocytes rather than neurons. Our results establish that both soluble and transmembrane molecular forms of TNF-alpha can play critical roles in vivo in the pathogenesis of CNS inflammation and demyelination, and validate TNF-alpha transgenic and mutant mice as important models for the further study of related human CNS diseases.
Probert
L
L
Department of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece. lesley_probert@prometheus.hol.gr
Akassoglou
K
K
Kassiotis
G
G
Pasparakis
M
M
Alexopoulou
L
L
Kollias
G
G
D000818:Animals; D002493:Central Nervous System Diseases / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000276:immunology*