Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity

Yujuan Su, Jinhao Xu, Ziai Zhu, Jisun Chin, Le Xu, Haoze Yu, Victoria Nudell, Barsha Dash, Esteban A. Moya, Li Ye, Axel Nimmerjahn and Xin Sun ()
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Yujuan Su: University of California San Diego
Jinhao Xu: University of California San Diego
Ziai Zhu: University of California San Diego
Jisun Chin: University of California San Diego
Le Xu: University of California San Diego
Haoze Yu: University of California San Diego
Victoria Nudell: Scripps Research Institute
Barsha Dash: La Jolla Institute for Immunology
Esteban A. Moya: University of California
Li Ye: Scripps Research Institute
Axel Nimmerjahn: The Salk Institute for Biological Studies
Xin Sun: University of California San Diego

Nature, 2024, vol. 631, issue 8021, 601-609

Abstract: 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 hyperreactivity1–3, 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+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ 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+ 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.

Date: 2024
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DOI: 10.1038/s41586-024-07608-5

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