Interleukin-1β enhances neuronal vulnerability to proNGF-mediated apoptosis by increasing surface expression of p75NTR and sortillin

Many types of injury such as seizure, ischemia, and oxidative stress cause upregulation of the p75 neurotrophin receptor (p75NTR) in brain neurons, where it promotes apoptosis, however the mechanism by which p75NTR 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 p75NTR induction both in neurons and astrocytes in vitro. Here, we show that IL-1β infusion into the brain induces p75NTR in neurons of the CA1 area of the hippocampus. While IL-1β induction of p75NTR is not sufficient to induce cell death, we demonstrate that IL-1β primes the neurons by recruiting p75NTR 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.