title: Substance P represents a novel first-line defense mechanism in the nose.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olivia
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Tengroth
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Otorhinolaryngology, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Uddman
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Kumlien Georén
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Department of ENT Diseases, Karolinska University Hospital, Stockholm, Sweden. Electronic address: lars-olaf.cardell@ki.se.
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D009297:Nasal Mucosa / Q000166:cytology / Q000276:immunology* / Q000294:innervation; D009475:Neurons, Afferent / Q000166:cytology / Q000276:immunology*; D013373:Substance P / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology
chemical_list: D008562:Membrane Glycoproteins; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D013373:Substance P
keywords: Toll-like receptor; Toll-like receptor 7; epithelial cells; innate immunity; nasal mucosa; substance P; viral infection