Cholinergic neuroplasticity in asthma driven by TrkB signaling

Author(s):Show less -

Dragunas, Guilherme ^{[1, 2, 3]} ; Woest, Manon E. ^{[2, 3]} ; Nijboer, Susan ^{[2, 3]} ; Bos, Sophie T. ^{[2, 3]} ; van Asselt, Janet ^{[2, 3]} ; de Groot, Anne P. ^{[2, 3]} ; Vohlidalova, Eva ^{[2, 3]} ; Vermeulen, Corneel J. ^{[2, 4]} ; Ditz, Benedikt ^{[2, 4]} ; Vonk, Judith M. ^{[2, 5]} ; Koppelman, Gerard H. ^{[2, 6]} ; van den Berge, Maarten ^{[2, 4]} ; ten Hacken, Nick H. T. ^{[2, 4]} ; Timens, Wim ^{[2, 7]} ; Munhoz, Carolina D. ^[1] ; Prakash, Y. S. ^[8] ; Gosens, Reinoud ^{[2, 3]} ; Kistemaker, Loes E. M. ^{[2, 3]}

Affiliation

^[1] Univ Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Groningen - Netherlands

^[3] Univ Groningen, Dept Mol Pharmacol, A Deusinglaan 1, NL-9713 AV Groningen - Netherlands

^[4] Univ Med Ctr Groningen, Dept Pulm Dis, Groningen - Netherlands

^[5] Univ Med Ctr Groningen, Dept Epidemiol, Groningen - Netherlands

^[6] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Dept Pediat Pulmonol & Pediat Allergol, Groningen - Netherlands

^[7] Univ Med Ctr Groningen, Dept Pathol, Groningen - Netherlands

^[8] Mayo Clin, Dept Anesthesiol & Perioperat Med, Rochester, MN - USA

• Document type: Journal article
• Source: FASEB JOURNAL; v. 34, n. 6, p. 7703-7717, JUN 2020.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 18/18762-8 - Stressing the lungs: neuronal plasticity in allergic airway inflammation
• Grantee: Guilherme Dragunas
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)