Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation

Among the chemokine family, fractalkine shows unusual properties: it exists as a membrane-bound and soluble protein, and both fractalkine and its rece ptor CX(3)CR1 are expressed predominantly in the central nervous system. In rat cell culture models, the chemokine fractalkine was expressed in neuron s and microglia, but not in astrocytes and its receptor exclusively localiz ed to microglial cells, where its expression was downregulated by treatment with the bacterial endotoxin (LPS). In microglial cultures, LPS (10 ng/ml) induced a marked increase in the release of the proinflammatory cytokine t umor necrosis factor-alpha (TNF-alpha). The effects of LPS on TNF-oc secret ion were partially blocked (30%) by fractalkine and the effects of fractalk ine were reversed by a polyclonal anti-fractalkine antibody. When microglia l-associated fractalkine was neutralized by anti-fractalkine antibody, the LPS response was increased by 80%, suggesting tonic activation of microglia l fractalkine receptors by endogenous fractalkine. The effects of the antib ody were antagonized by the addition of fractalkine. LPS-activated microgli a were neurotoxic when added to neuronal hippocampal culture, producing 20% neuronal death, as measured by NeuN-positive cell counting. An anti-fracta lkine antibody produced neurotoxic effects of similar magnitude in this co- culture system and also markedly potentiated the neurotoxic effects of LPS- activated microglia (40% neuronal death). These results suggest that endoge nous fractalkine might act tonically as an anti-inflammatory chemokine in c erebral tissue through its ability to control and suppress certain aspects of microglial activation. These data may have relevance to degenerative con ditions such as multiple sclerosis, in which cerebral inflammatory processe s may be activated. (C) 2000 Wiley-Liss, Inc.