Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways

Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11515-20. doi: 10.1073/pnas.1411032111. Epub 2014 Jul 21.

Abstract

Asthma is a common debilitating inflammatory lung disease affecting over 200 million people worldwide. Here, we investigated neurogenic components involved in asthmatic-like attacks using the ovalbumin-sensitized murine model of the disease, and identified a specific population of neurons that are required for airway hyperreactivity. We show that ablating or genetically silencing these neurons abolished the hyperreactive broncho-constrictions, even in the presence of a fully developed lung inflammatory immune response. These neurons are found in the vagal ganglia and are characterized by the expression of the transient receptor potential vanilloid 1 (TRPV1) ion channel. However, the TRPV1 channel itself is not required for the asthmatic-like hyperreactive airway response. We also demonstrate that optogenetic stimulation of this population of TRP-expressing cells with channelrhodopsin dramatically exacerbates airway hyperreactivity of inflamed airways. Notably, these cells express the sphingosine-1-phosphate receptor 3 (S1PR3), and stimulation with a S1PR3 agonist efficiently induced broncho-constrictions, even in the absence of ovalbumin sensitization and inflammation. Our results show that the airway hyperreactivity phenotype can be physiologically dissociated from the immune component, and provide a platform for devising therapeutic approaches to asthma that target these pathways separately.

Keywords: airway inflammation; bronchospasms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / complications
  • Asthma / pathology*
  • Asthma / physiopathology*
  • Bronchial Hyperreactivity / complications
  • Bronchial Hyperreactivity / pathology*
  • Bronchial Hyperreactivity / physiopathology*
  • Gene Deletion
  • Gene Silencing
  • Mice
  • Mice, Inbred C57BL
  • Pneumonia / complications
  • Pneumonia / pathology*
  • Pneumonia / physiopathology
  • Receptors, Lysosphingolipid / metabolism
  • Respiratory System / innervation*
  • Respiratory System / pathology
  • Respiratory System / physiopathology
  • Sensory Receptor Cells / metabolism
  • Sensory Receptor Cells / pathology*
  • TRPV Cation Channels / metabolism
  • Vagus Nerve / metabolism
  • Vagus Nerve / pathology

Substances

  • Receptors, Lysosphingolipid
  • TRPV Cation Channels
  • TRPV1 protein, mouse