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

Larsson, Olivia; Tengroth, Lotta; Xu, Yuan; Uddman, Rolf LU ; Kumlien Georén, Susanna and Cardell, Lars-Olaf LU (2017) In Journal of Allergy and Clinical Immunology
Abstract

Background: Neuropeptides, 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. Objectives: We sought to 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, with the latter reflected in changes in local Toll-like receptor (TLR) expression. Methods: The distribution of SP and TLRs in the nasal mucosa and local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to... (More)

Background: Neuropeptides, 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. Objectives: We sought to 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, with the latter reflected in changes in local Toll-like receptor (TLR) expression. Methods: The distribution of SP and TLRs in the nasal mucosa and local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in the upper airways represented by primary human nasal epithelial cells (HNECs) and murine nasal epithelial cells (MNECs) and isolated murine trigeminal ganglial neurons. SP release from HNECs, MNECs, and trigeminal ganglial neurons was quantified with EIA. The effects of SP on TLR expression on HNECs were determined by using flow cytometry and confocal microscopy. Results: SP was released from the sensory neurons, MNECs, and HNECs within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNECs within 30 minutes through induction of TLR movement within HNECs. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor antagonist aprepitant before SP stimulation. Conclusions: This highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Epithelial cells, Innate immunity, Nasal mucosa, Substance P, Toll-like receptor, Toll-like receptor 7, Viral infection
in
Journal of Allergy and Clinical Immunology
publisher
Elsevier
external identifiers
  • scopus:85019664752
ISSN
0091-6749
DOI
10.1016/j.jaci.2017.01.021
language
English
LU publication?
yes
id
713cd151-8e41-4043-bb7d-aa2562e11e14
date added to LUP
2017-06-27 09:21:13
date last changed
2017-06-27 09:21:13
@article{713cd151-8e41-4043-bb7d-aa2562e11e14,
  abstract     = {<p>Background: Neuropeptides, 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. Objectives: We sought to 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, with the latter reflected in changes in local Toll-like receptor (TLR) expression. Methods: The distribution of SP and TLRs in the nasal mucosa and local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in the upper airways represented by primary human nasal epithelial cells (HNECs) and murine nasal epithelial cells (MNECs) and isolated murine trigeminal ganglial neurons. SP release from HNECs, MNECs, and trigeminal ganglial neurons was quantified with EIA. The effects of SP on TLR expression on HNECs were determined by using flow cytometry and confocal microscopy. Results: SP was released from the sensory neurons, MNECs, and HNECs within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNECs within 30 minutes through induction of TLR movement within HNECs. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor antagonist aprepitant before SP stimulation. Conclusions: This highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway.</p>},
  author       = {Larsson, Olivia and Tengroth, Lotta and Xu, Yuan and Uddman, Rolf and Kumlien Georén, Susanna and Cardell, Lars-Olaf},
  issn         = {0091-6749},
  keyword      = {Epithelial cells,Innate immunity,Nasal mucosa,Substance P,Toll-like receptor,Toll-like receptor 7,Viral infection},
  language     = {eng},
  month        = {02},
  publisher    = {Elsevier},
  series       = {Journal of Allergy and Clinical Immunology},
  title        = {Substance P represents a novel first-line defense mechanism in the nose},
  url          = {http://dx.doi.org/10.1016/j.jaci.2017.01.021},
  year         = {2017},
}