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Brainstem Dbh + neurons control allergen-induced airway hyperreactivity.
- Source :
-
Nature [Nature] 2024 Jul; Vol. 631 (8021), pp. 601-609. Date of Electronic Publication: 2024 Jul 10. - Publication Year :
- 2024
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Abstract
- Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity <superscript>1-3</superscript> , the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh <superscript>+</superscript> nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh <superscript>+</superscript> nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh <superscript>+</superscript> nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh <superscript>+</superscript> nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Female
Male
Mice
Asthma immunology
Asthma physiopathology
Interleukin-4 immunology
Mast Cells immunology
Norepinephrine antagonists & inhibitors
Norepinephrine metabolism
Solitary Nucleus cytology
Solitary Nucleus physiology
Vagus Nerve cytology
Vagus Nerve physiology
Medulla Oblongata cytology
Medulla Oblongata drug effects
Ganglia, Autonomic cytology
Allergens immunology
Brain Stem cytology
Brain Stem physiology
Bronchial Hyperreactivity drug therapy
Bronchial Hyperreactivity immunology
Bronchial Hyperreactivity physiopathology
Lung drug effects
Lung immunology
Lung innervation
Lung physiopathology
Neurons enzymology
Neurons physiology
Dopamine beta-Hydroxylase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 631
- Issue :
- 8021
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38987587
- Full Text :
- https://doi.org/10.1038/s41586-024-07608-5