Cholinergic neuroplasticity in asthma driven by TrkB signaling

Area of Science:

• Neuroscience
• Pulmonology
• Immunology

Background:

• Parasympathetic neurons regulate airway tone, and their overactivity contributes to airway hyperresponsiveness (AHR) in asthma.
• The precise mechanisms underlying cholinergic neuron involvement in asthma pathogenesis remain incompletely understood.

Purpose of the Study:

• To investigate the role of brain-derived neurotrophic factor (BDNF) and Tropomyosin receptor kinase B (TrkB) signaling in the remodeling of cholinergic neurons in asthmatic airways.
• To explore the therapeutic potential of targeting the BDNF-TrkB pathway for asthma treatment.

Main Methods:

• Analysis of human bronchial biopsies for cholinergic markers (vesicular acetylcholine transporter - VAChT).
• Comparison of human lung gene expression and neuroplasticity-related gene single nucleotide polymorphisms (SNPs) between asthma patients and healthy individuals.
• Assessment of cholinergic nerve density and airway reactivity in mouse models of allergic asthma, including wild-type and TrkB-mutated mice, following chronic allergen exposure.

Main Results:

• Increased cholinergic nerve fibers were observed in asthmatic airway biopsies.
• Elevated TrkB gene expression and asthma-associated SNPs in BDNF and NTRK2 (TrkB) genes were found in human lung tissue.
• Chronic allergen exposure in mice led to increased cholinergic nerve density, which was attenuated by TrkB inhibition, resulting in AHR and enhanced nerve-dependent airway reactivity.

Conclusions:

• Cholinergic neuroplasticity, mediated by the BDNF-TrkB signaling pathway, plays a significant role in the pathophysiology of asthma.
• The BDNF-TrkB pathway represents a promising therapeutic target for managing airway hyperresponsiveness in asthma.