Abstract
BackgroundThe tachykinin substance P (SP) is recognized to exacerbate inflammation at peripheral sites via its target receptor, neurokinin 1 receptor (NK-1R), expressed by leukocytes. More recently, SP/NK-1R interactions have been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis. Furthermore, we have since shown that these agents can attenuate bacteria-induced neuronal and glial inflammatory mediator production in nonhuman primate (NHP) brain explants and isolated neuronal cells, and following in vivo infection.MethodsIn the present study, we have assessed the ability of NHP brain explants, primary human microglia and astrocytes, and immortalized human glial cell lines to express NK-1R isoforms. We have utilized RT-PCR, immunoblot analysis, immunofluorescent microscopy, and/or flow cytometric analysis, to quantify NK-1R expression in each, at rest, or following bacterial challenge. Furthermore, we have assessed the ability of human microglia to respond to SP by immunoblot analysis of NF-kB nuclear translocation and determined the ability of this neuropeptide to augment inflammatory cytokine release and neurotoxic mediator production by human astrocytes using an ELISA and a neuronal cell toxicity assay, respectively.ResultsWe demonstrate that human microglial and astrocytic cells as well as NHP brain tissue constitutively express robust levels of the full-length NK-1R isoform. In addition, we demonstrate that the expression of NK-1R by human astrocytes can be further elevated following exposure to disparate bacterial pathogens or their components. Importantly, we have demonstrated that NK-1R is functional in both human microglia and astrocytes and show that SP can augment the inflammatory and/or neurotoxic immune responses of glial cells to disparate and clinically relevant bacterial pathogens.ConclusionsThe robust constitutive and functional expression of the full-length NK-1R isoform by human microglia and astrocytes, and the ability of SP to augment inflammatory signaling pathways and mediator production by these cells, support the contention that SP/NK-1R interactions play a significant role in the damaging neuroinflammation associated with conditions such as bacterial meningitis.
Highlights
The tachykinin substance P (SP) is recognized to exacerbate inflammation at peripheral sites via its target receptor, neurokinin 1 receptor (NK-1R), expressed by leukocytes
The full-length NK-1R isoform is constitutively and robustly expressed in the nonhuman primate (NHP) brain, and SP levels are elevated following challenge with B. burgdorferi We have previously demonstrated the ability of an NK1R antagonist to ameliorate central nervous system (CNS) inflammation associated with in vivo CNS infection in a NHP model [10]
We have demonstrated the constitutive expression of full-length NK-1R protein by both a human microglial cell line and primary human microglia as determined by immunoblot analysis, immunohistochemical staining, and flow cytometry, at robust levels that could not be further elevated by exposure to bacterial ligands for TLR2, TLR4, or TLR5, either alone or in combination with SP treatment
Summary
The tachykinin substance P (SP) is recognized to exacerbate inflammation at peripheral sites via its target receptor, neurokinin 1 receptor (NK-1R), expressed by leukocytes. In addition to its functions as a neurotransmitter in the perception of pain and its essential role in gut motility, this tachykinin is recognized to exacerbate inflammation at peripheral sites including the skin, lung, and gastrointestinal and urogenital tracts This neuropeptide appears to contribute to disease pathology for some infectious agents. We have demonstrated that the specific NK-1R antagonist, aprepitant, limits inflammatory nervous system immune responses in a nonhuman primate (NHP) model of Lyme neuroborreliosis [10] These animal studies indicate that SP/NK-1R interactions are essential for the progression of damaging inflammation following bacterial CNS infection and raise the intriguing possibility that targeting the NK-1R could be useful as an adjunctive therapy for such conditions
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