Effects of allergen and airway constriction on gene expression in mouse lung
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212406 | GEO | 2022/11/18
REPOSITORIES: GEO
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Project description:Studying the proteomes of tissue-derived extracellular vesicles (EVs) can lead to the identifica-tion of biomarkers of disease and can provide a better understanding of cell-to-cell communica-tion in both healthy and diseased tissue. The aim of this study was to apply our previously es-tablished tissue-derived EV isolation protocol to mouse lungs in order to determine the changes in the proteomes of lung tissue-derived EVs during allergen-induced eosinophilic airway in-flammation. A mouse model for allergic airway inflammation was used by sensitizing the mice intraperitoneal with ovalbumin (OVA), and one week after the final sensitization, the mice were challenged intranasal with OVA or PBS. The animals were sacrificed 24 h after the final chal-lenge, and their lungs were removed and sliced into smaller pieces that were incubated in cul-ture media with DNase I and Collagenase D for 30 min at 37 °C. Vesicles were isolated from the medium by ultracentrifugation and bottom-loaded iodixanol density cushions, and the proteo-mes were determined using quantitative mass spectrometry. More EVs were present in the lungs of the OVA-challenged mice compared to the PBS-challenged control mice. In total, 4510 proteins were quantified in all samples. Among them, over 1000 proteins were significantly altered (fold change >2), with 614 proteins being increased and 425 proteins being decreased in the EVs from OVA-challenged mice compared to EVs from PBS-challenged animals. The associated cellular components and biological processes were analyzed for the altered EV proteins, and the proteins enriched during allergen-induced airway inflammation were mainly associated with gene on-tology (GO) terms related to immune responses. In conclusion, EVs can be isolated from mouse lung tissue, and the EVs’ proteomes undergo changes in response to allergen-induced airway in-flammation. This suggests that the composition of lung-derived EVs is altered in diseases asso-ciated with inflammation of the lung, which may have implications in type-2 driven eosino-philic asthma pathogenesis.
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Project description:Exaggerated airway constriction triggered by exposure to irritants such as allergen, also called hyperreactivity, is a hallmark of asthma and can be life-threatening. Aside from immune cells, vagal sensory neurons are important for airway hyperreactivity 1-4. However, the identity and signature of the downstream nodes of this adaptive circuit remains poorly understood. Here we show that Dbh+ neurons in the nucleus of the solitary tract (nTS) of the brainstem, and downstream neurons in the nucleus ambiguus (NA), are both necessary and sufficient for chronic allergen-induced airway hyperreactivity. We found that repeated exposures of mice to inhaled allergen activates nTS neurons in a mast cell-, interleukin 4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA-seq followed by RNAscope quantification of the nTS at baseline and following allergen challenges reveals that a Dbh+ population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted, while chemogenetic activation promoted hyperreactivity. Viral tracing indicates that Dbh+ nTS neurons, capable of producing norepinephrine, project to the NA, and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that then directly drive airway constriction. Focusing on transmitters, delivery of norepinephrine antagonists to the NA blunted allergen-induced hyperreactivity. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. The knowledge opens the possibility of targeting neural modulation as an approach to control refractory allergen-induced airway constriction.
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