Interleukin-1β enhances neuronal vulnerability to proNGF-mediated apoptosis by increasing surface expression of p75^NTR and sortillin

Many types of injury such as seizure, ischemia, and oxidative stress cause upregulation of the p75 neurotrophin receptor (p75^NTR) in brain neurons, where it promotes apoptosis, however the mechanism by which p75^NTR is regulated under these conditions is not well understood. Proinflammatory cytokines such as interleukin-1β (IL-1β) are highly produced under these injury conditions and, in particular, are expressed rapidly in the rat hippocampus after seizure. IL-1β is known to increase neuronal vulnerability under many conditions, although it does not directly induce neuronal death. Recently, we have shown that these cytokines regulate p75^NTR induction both in neurons and astrocytes in vitro. Here, we show that IL-1β infusion into the brain induces p75^NTR in neurons of the CA1 area of the hippocampus. While IL-1β induction of p75^NTR is not sufficient to induce cell death, we demonstrate that IL-1β primes the neurons by recruiting p75^NTR and its coreceptor sortilin to the cell surface, making the neurons more vulnerable to subsequent challenge by proNGF. These results suggest a mechanism by which IL-1β exacerbates neuronal death following injury.