Cholinergic neuroplasticity in asthma driven by TrkB signaling

Authors

DRAGUNAS G WOEST ME NIJBOER S BOS ST VAN Asselt J DE Groot AP VOHLÍDALOVÁ Eva VERMEULEN CJ DITZ B VONK JM KOPPELMAN GH VAN den Berge M TEN Hacken NHT TIMENS W MUNHOZ CD PRAKASH YS GOSENS R KISTEMAKER LEM

Year of publication 2020
Type Article in Periodical
Magazine / Source Faseb Journal
Citation
Doi http://dx.doi.org/10.1096/fj.202000170R
Keywords asthma; lung innervation; neuroplasticity; neurotrophins
Description 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.

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