Constitutive and inducible expression of the neurokinin-1 receptor for the inflammatory neuropeptide substance P in human microglia and astrocytes

Abstract

Abstract We have previously demonstrated that murine microglia and astrocytes express the neurokinin-1 high affinity receptor (NK-1R) for the neuropeptide substance P. Importantly, we have also shown that substance P/NK-1R interactions augment the inflammatory responses of isolated murine glia to bacterial challenge and exacerbate in vivo neuroinflammatory damage within the central nervous system in mouse models of meningitis. Here, we show the constitutive expression of NK-1R in acutely isolated non-human primate (NHP) brain tissue and ex vivo brain slices. Interestingly, NK-1R protein levels were increased in brain tissue as rapidly as 4 hours following ex vivo infection with Borrelia burgdorferi, the causative agent of Lyme neuroborreliosis. Furthermore, we observed higher NK-1R protein levels in NHP brain tissue at 2 and 4 weeks following in vivo infection, increases that correlated with decreases in the expression of glial fibrillary acidic protein. These in vivo changes were prevented by treatment with a specific NK-1R antagonist suggesting a key role for substance P/NK-1R interactions in these effects. We then investigated the expression of NK-1R in human glial cells. While human microglia showed robust NK-1R expression at rest, astrocytes constitutively expressed only low levels. However, challenge with bacteria or their products elicited rapid increases in whole cell and cell surface NK-1R protein expression by primary human astrocytes and cell lines. Together, these data indicate that human microglia and astrocytes show constitutive and/or inducible expression of the substance P receptor and may therefore be susceptible to this pro-inflammatory neuropeptide.