While glial cells are recognized for their roles in maintaining neuronal function, there is growing appreciation of the ability of resident glial cells to initiate and/or augment inflammation following trauma or infection in the central nervous system (CMS). However, the mechanisms that underlie the inflammatory responses of glial cells have yet to be defined. The tachykinin, substance P, is found throughout the CMS, with evidence for both neuronal and glial cells as being sources of this neuropeptide. Substance P is well known to augment inflammatory responses at peripheral sites, such as the gastrointestinal tract and skin. Its documented ability to augment microbially induced inflammation, and the presence of moderate to high levels of substance P in many regions of the CMS, leads us to hypothesize that this tachykinin serves a similar function within the brain. Neurokinin-1 (NK-1) receptors have a high affinity for substance P and have recently been demonstrated in a number of resident CMS cell types, including astrocytes and microglia. To date, the actions of substance P on glial cells are poorly understood, and the ability of this neuropeptide to regulate the immune functions of resident CMS cells initiated by microbial challenge has not been investigated. The experiments described in this proposal will assess the ability of substance P to regulate the inflammatory immune functions of microglia and astrocytes following challenge with disparate, and clinically relevant, bacterial and viral pathogens. The ability of substance P to alter glial production of key inflammatory mediators following exposure to these pathogens and the mechanisms that underlie such effects will be assessed in vitro utilizing isolated astrocyte and microglial cell cultures. Importantly, we will investigate the role played by substance P/NK-1 receptor interactions in glial immune responses in vivo following pathogen administration into the CMS. The specificity of such effects will be demonstrated using non-peptide NK-1 receptor antagonists and mice genetically deficient in the expression of this receptor. A demonstration of the ability of substance P/substance P receptor interactions to augment pathogen-induced immune responses of glial cells will reveal a previously unappreciated role for this endogenous neuropeptide during CMS infections and will contribute significantly to our understanding of the events that underlie the development of protective host responses within the brain or, alternatively, the progression of damaging CMS inflammation. Furthermore, amelioration of microbially induced neurological damage by systemically administered non-peptide NK-1 receptor antagonists of a type that are currently under investigation as anti-depression and anxiolytic therapies in human patients will have important translational implications for the design of novel treatment strategies for human inflammatory CMS disorders.
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