Exacerbation of human astrocyte inflammatory responses to bacterial pathogens by the neuropeptide substance P (MPF2P.742)

Abstract

The neuropeptide substance P (SP) has increasingly been recognized to augment inflammatory immune responses. We have recently demonstrated that SP can significantly exacerbate the inflammatory responses of isolated murine glial cells to clinically relevant bacterial pathogens. Furthermore, we have shown that SP interactions with its receptor are an essential component in the initiation and/or progression of central nervous system (CNS) inflammation in in vivo mouse models of meningitis. In the present study, we demonstrate that SP similarly alters the inflammatory responses of human astrocytes to clinically relevant bacterial pathogens and their components. Specifically, we show that SP augments the production of inflammatory cytokines and the generation of nitric oxide by human astrocytes in response to Neisseria meningitidis. In addition, we showed that this effect is seen in astrocyte responses to the TLR4 ligand, LPS. However, such SP-mediated increases in inflammatory mediator production are not limited to TLR4 stimuli as human astrocyte responses to the disparate Gram-negative bacterial pathogen Borrelia burgdorferi, that does not express LPS, are also modulated in a dose and time dependent manner. Together, these results suggest that SP could play a significant role in the initiation and/or progression of bacterially induced CNS inflammation in humans in a similar manner to that previously seen in rodent models following infection.