Review Article

Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity

Figure 1

Proposed mechanisms by which TNF-α links the neuroinflammatory and the excitotoxic processes. The cytokine IFN-γ, released by infiltrated T cells, activates TNF-α production and release in microglia. TNF-α, through TNFR1 signaling, promotes further microglial TNF-α release and also induces glutamate release from hemichannels of gap junctions. In astrocytes, TNF-α stimulates TNFR1 to induce glutamate exocytosis and also inhibits glutamate uptake, thus increasing extracellular glutamate levels. In neurons TNF-α, via TNFR1, rapidly increases the excitatory synaptic strength by inducing increased Ca2+ permeable-AMPA receptors and/or NMDA receptors and also decreases the surface expression of inhibitory GABAA receptors. The excessive Ca2+ input to neurons induces neuronal death and generates excessive ROS that disrupt glutamate transport in neighboring astrocytes. The dying neurons maintain microglia in an active state, releasing TNF-α.
861231.fig.001