Substance P represents a novel first-line defense mechanism in the nose

Publication date: Available online 20 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Olivia Larsson, Lotta Tengroth, Yuan Xu, Rolf Uddman, Susanna Kumlien Georén, Lars-Olaf Cardell
BackgroundNeuropeptides, such as substance P (SP), have long been seen as mediators of widespread, continuous airway inflammation, a process known as neurogenic inflammation. However, this has been difficult to demonstrate clinically, suggesting an alternative role for these signaling molecules.ObjectivesTo examine the role of SP in nasal infection, by assessing the release of SP in response to viral stimulation and characterizing the effects of SP on innate immunity, the latter reflected in changes in local Toll-like receptor (TLR) expression.MethodsThe distribution of SP and TLRs in the nasal mucosa and in local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in upper airways, represented by primary human and mouse nasal epithelial cells (HNEC, MNEC) and isolated murine trigeminal ganglia (TGN). SP release from HNEC, MNEC and TGN was quantified with EIA. The effects of SP on TLR expression on HNEC were determined using flow cytometry and confocal microscopy.ResultsSP was released from the sensory neurons, MNEC and HNEC within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNEC within 30 minutes, via induction of TLR movement within HNEC. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor (NK1R) antagonist aprepitant prior to SP stimulation.ConclusionsThis highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway.

Graphical abstract

Teaser

Toll-like receptors (TLRs) and substance P (SP) have both been shown to contribute to airway disease, particularly during viral infection. The present paper demonstrates a novel role for SP in kick-starting the TLR-driven immune response.


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