Cytokines reprogram airway sensory neurons in asthma

Area of Science:

• Neuroscience
• Immunology
• Respiratory Medicine

Background:

• Nociceptor neurons detect environmental dangers but contribute to allergic reactions.
• Vagal nociceptors promote immune cell infiltration and bronchial hypersensitivity in allergies.
• Mechanisms of nociceptor pro-inflammatory reprogramming in allergies remain unclear.

Purpose of the Study:

• Investigate molecular profile changes in airway nociceptors during allergic inflammation.
• Identify signals driving nociceptor reprogramming in allergic airway inflammation.
• Characterize the role of Neuropeptide Y receptor 1 (NPY1R) in this process.

Main Methods:

• Retrograde tracing and lineage reporting in a mouse model.
• Ovalbumin-induced allergic airway inflammation model.
• Screening of cytokines and neurotrophins, including IL-13 and BDNF.
• Single-cell RNA sequencing of lung immune cells.
• NPY1R knockout and chemical ablation of nociceptor neurons.

Main Results:

• Identified a specific class of inflammatory vagal nociceptors innervating airways.
• Discovered Neuropeptide Y receptor 1 (NPY1R) upregulation in these neurons.
• IL-13, IL-1β, and BDNF partially drive nociceptor reprogramming via JAK/STAT6 pathway.
• Neuropeptide Y (NPY) release in bronchoalveolar fluid limits nociceptor excitability.
• NPY1R knockout in nociceptors altered T cell infiltration in asthmatic mice.

Conclusions:

• Allergic airway inflammation reprograms airway nociceptor neurons to a pro-inflammatory phenotype.
• A compensatory mechanism involving NPY1R activation limits nociceptor neuron activity.
• Targeting NPY1R may offer therapeutic strategies for allergic airway diseases.