Allergen-induced vital DNA release by the airway epithelium amplifies type-2 immunity
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PROVIDER: PRJNA816531 | ENA |
REPOSITORIES: ENA
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Project description:This study has several novel aspects that address molecular mechanisms underlying type 2 immunity and allergic inflammation. We have identified a previously unknown response of human airway epithelial cells to allergens that involves rapid mobilization and release of nuclear DNA (nDNA) from epithelial cells that remain viable throughout the duration of exposure. We show that nDNA release occurs across the apical membrane, but not the basolateral membrane and that sequence analysis of the secreted DNA reveals proportionally higher amounts of promotor and exon sequences and lower intron and intergenic sequences compared to the normal distributions of these regions in the intact genome. Furthermore, unlike DNA release during NETosis, the extracellular DNA is highly fragmented, ranging in size from 1000-5000 bp. We discovered that allergen exposure stimulates caspase 3 by a non-canonical mechanism involving calcium-dependent activation of furin and that caspase 3 activity leads to DNA fragmentation as shown in comet assays. Using a mouse model of allergic inflammation, we demonstrate that allergen-induced type 2 immune responses are markedly reduced by pretreatment with a DNA scavenger and that nDNA release was significantly reduced in mice that were caspase 3 deficient. Moreover, we show that intranasal treatment with mouse genomic DNA combined with submaximal exposure to allergens amplified secretion of Th2 cytokines into bronchoalveolar lavage fluid while DNA alone had no effect. These results highlight a novel, allergen-dependent mechanism of regulated and rapid nDNA mobilization and release that amplifies type 2 immunity in airways and suggests that pharmacotherapies targeting this mechanism may be beneficial in reducing allergic inflammation and exacerbation of asthma.
2022-10-01 | GSE198721 | GEO
Project description:Changes occur in the lung epithelium after allergen challenge that may give insight into asthma pathogenesis and we sought to identify novelepithelial genes induced by allergen exposure. We used microarrays to identify up-regulated genes induced by allergen challenge in lung epithelium. Epithelal brushing of the large airways in mouse lungs was performed 24 hours after Alternaria allergen or PBS control challenge 24. Collected epithelial cells underwent RNA extraction and hybridization on Affymetrix microarrays. There are a total of 6 samples, 3 allergen and 3 control samples.
2011-12-30 | E-GEOD-34764 | biostudies-arrayexpress
Project description:Changes occur in the lung epithelium after allergen challenge that may give insight into asthma pathogenesis and we sought to identify novelepithelial genes induced by allergen exposure. We used microarrays to identify up-regulated genes induced by allergen challenge in lung epithelium.
2011-12-30 | GSE34764 | 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 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: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:Response to allergen was studied in bronchial epithelial cell line H292. Cells were cultured and subsequently exposed to House dust mite or vessel (saline) Microarray data was analysed using bioinformatics and biostastics. We find a strong response to allergen in epithelial cells Keywords: cellular response to allergen
2007-10-01 | GSE9151 | GEO
Project description:Background: Airway epithelium in patients with allergic airway disease actively releases and is subjected to the influence of type-2 cytokines with observable changes in basal epithelial cells. Symptoms that grass pollen-allergic patients experience due to this priming can be controlled by allergen-specific immunotherapy (AIT). However, the impact of AIT on type-2 related mediators of airway epithelial cells is unknown. Methods: Protein levels of type-2 cytokines in nasal secretions of grass pollen-allergic patients were analyzed during 3-year AIT-regimen using multiplex-ELISA. Source and IL-4-dependence of type-2 cytokines were examined in IL-4-primed primary ALI cultures using single-cell transcriptomics. Results: Type-2 cytokines CCL-26 and POSTN oscillated seasonally, derived from basal epithelial cells and were induced by IL-4-priming. In contrast, TSLP and IL-33 derived from basal cells, albeit independently of IL-4. POSTN and IL-24 nasal levels changed corresponding to 3-year AIT progression. Four characteristic epithelial type-2 cytokines stood out: IL-33 changed independent of season, IL-4-exposure, or AIT; CCL-26 was triggered upon IL-4-priming and was induced during pollen season, but not influenced by AIT; IL-24 decreased following three years of AIT; and POSTN, which was increased in IL-4-primed basal epithelial cells and oscillated during pollen season, also responded to long-term AIT. Conclusions: Atopic reprogramming of type-2 epithelial cytokines seems to persist despite long-term AIT, which may be one mechanism explaining why AIT only restores allergen tolerance for seven to ten years. Type-2 related epithelial cytokines are differentially expressed which may relate to the distinct expression of basal as opposed to differentiated secretory or ciliated epithelial cells.
2023-03-31 | GSE203248 | GEO
Project description:Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity
| PRJNA870768 | ENA