Regulation and Relevance of Neuron-Specific Interferon Signaling Pathways

Rall, Glenn

Abstract

Neuroinflammation can occur as a consequence of neurotropic viral infection, brain tumor, traumatic brain injury, or autoimmunity, and the prognoses pursuant to these events are often poor. Despite the prevalence of diseases in which neuroinflammation may be a key component of damage, little is known about how cytokines, including interferons (IFNs), affect neuronal physiology. Moreover, virtually nothing is known about the IFN response in distinct neuronal sub-populations (based on either location or function). In preliminary studies, we showed that primary hippocampal neurons express less of the key IFN signal transducer, STAT1, than do non-neuronal cells, including primary fibroblasts and astrocytes. In fact, while interferon-gamma (IFN?) is necessary for protection from an otherwise lethal neurotropic measles virus infection, STAT1 is not required for mouse survival or viral clearance. These data, the first to decouple STAT1 from IFN? signaling, imply that alternative signaling pathways are utilized in neurons. Our recent work indicates that other signal transducers are disproportionately induced in neurons, which we speculate results in the activation of a pro-survival program that braces the neuron from neuroinflammatory cytotoxicity. This proposal pursues two complementary aims to test the hypothesis that cell- intrinsic differences in the expression levels of signal transducers can diversify the cellular response to a given cytokine ligand. Our objective is to characterize the IFN? signaling pathways in neurons, to show how use of alternative (non-STAT1-mediated) pathways affects viral clearance and neuronal biology, and to identify how differences in neuronal subtype may contribute to a more sophisticated understanding of inflammation in the brain. Ultimately, these studies will provide a foundation upon which to build rational strategies to prevent or treat life-threatening brain disorders.

Public Health Relevance

A growing literature supports the assertion that the cellular response to cytokines is cell type-specific. We have shown that neurons, both in culture and in whole brains, respond distinctly to the potent antiviral cytokine, interferon-gamma, inducing a pro-survival program that is not observed in most other cell types. In this proposal, we explore the basis of this differential response, define how neuronal sub-populations may contribute to an even more complex response profile, and ultimately, determine how cell-specific cytokine pathways impact infection and inflammation within the central nervous system.