BDNF-TrkB signaling mediates cholinergic neuroplasticity in asthma

Guilherme Dragunas, Manon Woest, Susan Nijboer - Brinksma, Isabella Bos, Cornelis Vermeulen, Lars Ditz, J. M. Vonk, Gerard Koppelman, Maarten van den Berge, Nick H.T. ten Hacken, Wim Timens, Carolina Demarchi Munhoz, Y S Prakash, Reinoud Gosens, Loes Kistemaker



Background: Abnormal neuronal activity contributes to symptoms of allergic asthma, where increased cholinergic tone is observed. Neurotrophins such as brain-derived neurotrophic factor (BDNF) are target-derived neuronal growth factors and increasingly recognized as important in asthma. Here we hypothesized that there is an increased cholinergic neuronal density in asthmatic airways mediated by BDNF signaling via its receptor TrkB.

Methods: Human bronchial biopsies were stained for the 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 (TrkBKI) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal PGP9.5 and VAChT staining and airway narrowing in lung slices were assessed.

Results: Compared to healthy subjects, bronchial biopsies from asthma patients showed a 1.6 fold higher VAChT+ area. Human lung transcriptome analysis revealed TrkB gene expression 1.5 fold higher in asthma versus healthy. Moreover, 5 SNPs in the BDNF gene and 1 SNP in the TrkB gene were associated with asthma. WT mice displayed a 2.0 fold increase in PGP9.5 and 1.8 fold increase in VAChT+ area, which were not observed in TrkBKI. Furthermore, airway hyperresponsiveness, as seen in WT mice, was not observed in TrkBKI.

Conclusion: Our results indicate that in human asthma and in OVA exposed mice, an increased cholinergic nerve fiber density is present. The BDNF-TrkB signaling pathway might be involved in this neuroplasticity and genetic variation in both genes may contribute to asthma susceptibility.
Originele taal-2English
Aantal pagina's2
TijdschriftEuropean Respiratory Journal
Nummer van het tijdschrift63
StatusPublished - 28-sep-2019
EvenementERS International congres 2019 - Madrid, Spain
Duur: 28-sep-20192-okt-2019

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