Control of Microglial Neurotoxicity by the Fractalkine Receptor
Cardona, A.E., Pioro, E.P., Sasse, M.E., Kostenko, V., et al. Nature Neuroscience, 9(7), 917-924 (July, 2006).
In response to injury, microglia change morphologically and acquire properties of mature myeloid cells, including matrix metalloproteinase expression, phagocytosis, and cytokine secretion. Their potential involvement in neurotoxicity was studied in three in vivo models:
Systemic administration of the inflammatory agent lipopolysaccharide was found to activate microglia in mice lacking a functional CX3CR1 (or fractalkine) receptor. Implantation of the activated microglia into wild-type mice further showed that the cells do not migrate, as normal cells do, but cause neuronal death via an IL-1 mediated pathway.
MPTP, which is used as a model to study Parkinsonís disease, was found to have a more pronounced neurotoxic effect on tyrosine hydroxylase-containing neurons of the substantia nigra in mice lacking the functional CX3CR receptor.
Transgenic mice that overexpress a mutant form of the human gene for superoxide dismutase are a model for studying age-dependent degeneration of motor neurons related to amyotrophic lateral sclerosis. Such mice lacking the functional CX3CR1 receptor were found to be more susceptible to the inflammatory/neurodegenerative process, as indicated by a faster loss of hindlimb grip strength and shorter survival.
The results point to an involvement of the CX3CL1-CX3CR1 signaling pathway in the central nervous systemís response to inflammatory and other neurodegenerative stimuli. Neuronal release of the chemokine CX3CL1 appears to restrain the neurotoxic capabilities of microglia under normal circumstances. Hence, this pathway may provide a new approach to combating neurodegenerative diseases.
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