Cholinergic neuroplasticity in asthma driven by TrkB signaling

Guilherme Dragunas*, Manon E Woest, Susan Nijboer, Sophie T Bos, Janet van Asselt, Anne P de Groot, Eva Vohlídalová, Corneel J Vermeulen, Benedikt Ditz, Judith M Vonk, Gerard H Koppelman, Maarten van den Berge, Nick H T Ten Hacken, Wim Timens, Carolina D Munhoz, Y S Prakash, Reinoud Gosens, Loes E M Kistemaker

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Parasympathetic neurons in the airways control bronchomotor tone. Increased activity of cholinergic neurons are mediators of airway hyperresponsiveness (AHR) in asthma, however, mechanisms are not elucidated. We describe remodeling of the cholinergic neuronal network in asthmatic airways driven by brain-derived neurotrophic factor (BDNF) and Tropomyosin receptor kinase B (TrkB). Human bronchial biopsies were stained for cholinergic marker vesicular acetylcholine transporter (VAChT). Human lung gene expression and single nucleotide polymorphisms (SNP) in neuroplasticity-related genes were compared between asthma and healthy patients. Wild-type (WT) and mutated TrkB knock-in mice (Ntrk2tm1Ddg/J) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal VAChT staining and airway narrowing in response to electrical field stimulation in precision cut lung slices (PCLS) were assessed. Increased cholinergic fibers in asthmatic airway biopsies was found, paralleled by increased TrkB gene expression in human lung tissue, and SNPs in the NTRK2 [TrkB] and BDNF genes linked to asthma. Chronic allergen exposure in mice resulted in increased density of cholinergic nerves, which was prevented by inhibiting TrkB. Increased nerve density resulted in AHR in vivo and in increased nerve-dependent airway reactivity in lung slices mediated via TrkB. These findings show cholinergic neuroplasticity in asthma driven by TrkB signaling and suggest that the BDNF-TrkB pathway may be a potential target.

Original languageEnglish
Pages (from-to)7703-7717
Number of pages15
JournalThe FASEB Journal
Volume34
Issue number6
Early online date11-Apr-2020
DOIs
Publication statusPublished - Jun-2020

Keywords

  • asthma
  • lung innervation
  • neuroplasticity
  • neurotrophins
  • NEUROTROPHIC FACTOR
  • AIRWAY HYPERRESPONSIVENESS
  • GENOMEWIDE ASSOCIATION
  • ALLERGEN EXPOSURE
  • LUNG-SLICE
  • TIOTROPIUM
  • RECEPTORS
  • INNERVATION
  • DYSFUNCTION
  • EXPRESSION

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