Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity
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ABSTRACT:
PROVIDER: PRJNA870768 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21120248_1.fastq.gz | Fastqsanger.gz | |||
| SRR21120248_2.fastq.gz | Fastqsanger.gz |
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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 allergen-induced airway constriction.
2024-04-15 | GSE200003 | GEO
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.
2024-04-15 | GSE211538 | GEO
Project description:Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity
| PRJNA822428 | ENA
Project description: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.
| S-EPMC11254774 | biostudies-literature
Project description:Mice representing phenotypic extremes of airway hyperreactivity and goblet cell metaplasia post-Sendai virus infection were identified from a 500 mouse F2 cohort (CB6F2/J). Whole lung RNA from 3 mice at each extreme was analyzed via microarray for gene expression. Subsequent pairwise comparisons between arrays allowed the identification of genes differentially expressed with respect to the disease phenotypes (airway hyperreactivity and goblet cell metaplasia). Keywords: disease state analysis
2006-03-30 | GSE3925 | GEO
Project description:Allergen exposure induces the airway epithelium to produce chemoattractants, proallergic interleukins, matrix-modifying proteins, and proteins that influence the growth and activation state of airway structural cells. These proteins, in turn, contribute to the influx of inflammatory cells and changes in structure that characterize the asthmatic airway. To use the response of the airway epithelium to allergen to identify genes not previously associated with allergic responses, we compared gene expression in cytokeratin-positive cells before and after segmental allergen challenge. After challenge with concentrations of allergen in the clinically relevant range, 755 (6%) of the detectable sequences had geometric mean fold-changes in expression, with 95% confidence intervals that excluded unity. Using a prospectively defined conservative filtering algorithm, we identified 141 sequences as upregulated and eight as downregulated, with confirmation by conventional polymerase chain reaction in all 10 sequences studied. Using this approach, we identified asthma-associated sequences including interleukin (IL-)-3, IL-4, and IL-5 receptor subunits, the p65 component of nuclear factor-kappaB, and lipocortin. The genomic response of the human airway to concentrations of allergen in the clinically relevant range involves a greater number of genes than previously recognized, including many not previously associated with asthma that are differentially expressed after airway allergen exposure. Keywords: Before and after allergen challenge
2005-08-01 | GSE3004 | GEO
Project description:Allergen exposure induces the airway epithelium to produce chemoattractants, proallergic interleukins, matrix-modifying proteins, and proteins that influence the growth and activation state of airway structural cells. These proteins, in turn, contribute to the influx of inflammatory cells and changes in structure that characterize the asthmatic airway. To use the response of the airway epithelium to allergen to identify genes not previously associated with allergic responses, we compared gene expression in cytokeratin-positive cells before and after segmental allergen challenge. After challenge with concentrations of allergen in the clinically relevant range, 755 (6%) of the detectable sequences had geometric mean fold-changes in expression, with 95% confidence intervals that excluded unity. Using a prospectively defined conservative filtering algorithm, we identified 141 sequences as upregulated and eight as downregulated, with confirmation by conventional polymerase chain reaction in all 10 sequences studied. Using this approach, we identified asthma-associated sequences including interleukin (IL-)-3, IL-4, and IL-5 receptor subunits, the p65 component of nuclear factor-{kappa}B, and lipocortin. The genomic response of the human airway to concentrations of allergen in the clinically relevant range involves a greater number of genes than previously recognized, including many not previously associated with asthma that are differentially expressed after airway allergen exposure. <br><br> NOTE: There is no subject #4 in this series (subject 4 was excluded based on clinical criteria). [For references see publication: Lilly et al., Am J Respir Crit Care Med. 2005 Mar 15;171(6):579-86]
2007-11-21 | E-GEOD-3004 | biostudies-arrayexpress
Project description:Bronchial asthma is associated with type 2 immune responses induced by components of adaptive as well as innate immunity. Although innate cytokines such as IL-25 have been shown to play key roles in development of airway hyperreactivity (AHR), little is known of innate molecules that regulate IL-25-mediated airway inflammation. We found that blockade of repulsive guidance molecule b (RGMb) in an experimental murine model of asthma blocked the development of AHR, a cardinal feature of asthma, and that RGMb is expressed on F4/80+CD11b+CD11cneg macrophages (RGMb+ macrophages), which accumulated in the lungs of OVA-sensitized and challenged mice, but not in naïve mice. Moreover, we found that a large fraction of the RGMb+ macrophages expressed the IL-25 receptor IL-17RB and produced IL-13. IL-25 was critical for the development of AHR in our model, since mice deficient in IL-17RB did not develop AHR. Finally, treatment with anti-RGMb mAb during the challenge phase of the protocol after allergen sensitization effectively prevented the development of AHR and airway inflammation, suggesting for the first time that RGMb+ cells, including RGMb+ macrophages, play critical roles in allergen-induced asthma. We used microarrays to compare the gene expression patterns in WT mice sensitized and challenged with OVA that were treated with either RGMb mAb or an isotype control. First replicate: 3 control samples (mice sensitized and challenged with saline), 3 RGMb mAb samples, 3 isotype samples; 2nd replicate: 3 control samples, 3 RGMb mAb samples, 2 isotype samples. Lung tissues were harvested at the same treatment time point in all groups.
2016-03-14 | E-GEOD-79156 | biostudies-arrayexpress
Project description:Bronchial asthma is associated with type 2 immune responses induced by components of adaptive as well as innate immunity. Although innate cytokines such as IL-25 have been shown to play key roles in development of airway hyperreactivity (AHR), little is known of innate molecules that regulate IL-25-mediated airway inflammation. We found that blockade of repulsive guidance molecule b (RGMb) in an experimental murine model of asthma blocked the development of AHR, a cardinal feature of asthma, and that RGMb is expressed on F4/80+CD11b+CD11cneg macrophages (RGMb+ macrophages), which accumulated in the lungs of OVA-sensitized and challenged mice, but not in naïve mice. Moreover, we found that a large fraction of the RGMb+ macrophages expressed the IL-25 receptor IL-17RB and produced IL-13. IL-25 was critical for the development of AHR in our model, since mice deficient in IL-17RB did not develop AHR. Finally, treatment with anti-RGMb mAb during the challenge phase of the protocol after allergen sensitization effectively prevented the development of AHR and airway inflammation, suggesting for the first time that RGMb+ cells, including RGMb+ macrophages, play critical roles in allergen-induced asthma. We used microarrays to compare the gene expression patterns in WT mice sensitized and challenged with OVA that were treated with either RGMb mAb or an isotype control.
2016-03-14 | GSE79156 | GEO
Project description:Allergen challenge induced mucus metaplasia modify the expression of two transcription factors belonging to the FOXA family: FOXA2 and FOXA3. Foxa2 expression is decreased during allergic airway disease whereas, Foxa3 expression is increased by allergen. Therefore, we asked whether persistent expression of Foxa2 prevents mucus and whether absence of Foxa3 affects mucus or other features asociated with allergic airway disease. We analyzed the effects of these changes in FOXA transcription factor expression using Foxa2 transgenic mice and Foxa3-/- mice. We found that persistent expression of FOXA2 reduced mucus but the absence of FOXA3 had no effect on mucus production induced by allergen challenge. However, the absence of FOXA3 decreased airway hyperreactivity and increased IgE production and eosinophilic inflammation but none of these features were affected by persistent expression of FOXA2. These results indicate that FOXA3 has functions distinct from those of FOXA2 in the allergic response. Keywords: gene expression comparison between Foxa3-/- and littermate control mice both challenged with OVA
2009-08-21 | GSE13382 | GEO