Cholinergic neuroplasticity in asthma driven by TrkB signaling.

Apr 12, 2020

Contributor: 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

Cholinergic neuroplasticity in asthma driven by TrkB signaling.

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.
© 2020 The Authors. The FASEB Journal published by Wiley periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

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About The Expert

Guilherme Dragunas

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Pharmacology, University of São Paulo, São Paulo, Brazil.

Manon E Woest

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Susan Nijboer

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Sophie T Bos

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Janet van Asselt

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Anne P de Groot

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Eva Vohlídalová

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Corneel J Vermeulen

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Pulmonary Diseases, UMCG, Groningen, the Netherlands.

Benedikt Ditz

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Pulmonary Diseases, UMCG, Groningen, the Netherlands.

Judith M Vonk

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Epidemiology, UMCG, Groningen, the Netherlands.

Gerard H Koppelman

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, University of Groningen, Beatrix Children’s Hospital, Groningen, the Netherlands.

Maarten van den Berge

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Pulmonary Diseases, UMCG, Groningen, the Netherlands.

Nick H T Ten Hacken

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Pulmonary Diseases, UMCG, Groningen, the Netherlands.

Wim Timens

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Pathology, UMCG, Groningen, the Netherlands.

Carolina D Munhoz

Department of Pharmacology, University of São Paulo, São Paulo, Brazil.

Y S Prakash

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.

Reinoud Gosens

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Loes E M Kistemaker

Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands.

GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

References

PubMed