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Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE211538 | GEO | 2024/04/15

REPOSITORIES: GEO

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Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity

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

A vagal reflex evoked by airway closure

Project description:Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and on a moment-by-moment basis, enact vital reflexes to maintain respiratory function. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax, or airway compression. Here, we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses, and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, while ablating NEBs or vagal PVALB neurons eliminated gasping to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of PIEZO2 in NEBs also eliminated responses to airway closure. NEBs are dispensable for the Hering-Breuer inspiratory reflex, indicating that discrete terminal structures detect airway closure and inflation. Like Merkel cells involved in touch sensation, NEBs are PIEZO2-expressing epithelial cells, and moreover, are critical for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways, and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function.

2024-03-06 | GSE252735 | GEO

Hypothalamic and dorsal vagal glucose-dependent insulinotropic polypeptide receptor (GIPR) neurons employ distinct mechanisms to affect feeding

Project description:Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signalling is critical for GIP-based therapeutics to lower body weight, but pathways leveraged by GIPR agonism pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC)—brain regions critical to the control of energy balance. Hypothalamic expression of Gipr expression was not necessary for the synergistic effect of GIPR/ agonism combined with GLP-1R co-agonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (SAGIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to the parabrachial nucleus and paraventricular hypothalamic nucleusdistal brain regions. ScRNAseq and FISH analysis showed that Gipr neurons in the NTS and AP Gipr neurons were transcriptomically distinct. Peripherally-dosed fluorescent GIPR agonists (GIPRAs) revealed that GIPRA access was restricted to circumventricular organs in the CNS. Together tThese data demonstrate that while the hypothalamus, AP and NTS are key sites for Gipr expression, these subpopulations of Gipr neurons in the hypothalamus, AP and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility to peripherally administered GIPRAs, and the appetite controlling pathways they employ. These results highlight the heterogeneity of the central GIPR signalling axis, and suggest that studies aimed at understandinginto the effects of GIP pharmacology on feeding behaviour should consider the interplay of multiple regulatory pathways.

2023-04-07 | GSE228192 | GEO

An airway protection program revealed by sweeping genetic control of vagal afferents

Project description:Sensory neurons evoke a suite of defensive reflexes to ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia, and choking, yet relevant sensory pathways remain poorly understood. Here, we discover rare throat-innervating neurons (~100 neurons/mouse) that guard the airways against assault. We used genetic tools that broadly cover a vagal/glossopharyngeal sensory neuron atlas to map, ablate, and control specific afferent populations. Optogenetic activation of vagal P2RY1 neurons evokes a coordinated airway defense program- apnea, vocal fold adduction, swallowing, and expiratory reflexes. Selective ablation of vagal P2RY1 neurons eliminates protective responses to laryngeal water and acid challenge. Anatomical mapping revealed numerous terminal morphologies in the larynx, with P2RY1 neurons forming corpuscular endings that appose laryngeal taste buds. Epithelial cells are primary airway sentinels that communicate with second-order P2RY1 neurons through ATP. These findings provide mechanistic insights into airway defense, and a general molecular/genetic roadmap for internal organ sensation by the vagus nerve.

2020-04-05 | GSE145216 | GEO

Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism

Project description:Agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combined non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons allowing to compare metabolic responses in mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. These experiments revealed that food intake is regulated by the additive effect of AgRP-neuron activation and POMC-neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated versus simultaneous regulation of AgRP and POMC neurons. We identified a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH), where activated AgRP- and inhibited POMC neurons synergize to promote food consumption and activate neurons in the nucleus tractus solitarii (NTS). We then performed single-nuclei RNA sequencing to define the molecular nature of Fos+ cells in the posterior NTS/AP area that respond to simultaneous chemogenetic intervention over AgRP and POMC neurons and identified TH+ neurons as candidates for receiving neuronal inputs initiated by the simultaneous and coordinated interplay between AgRP and POMC neurocircuits and relayed to the NTS area by the silenced glutamatergic Npy1R neurons.

2024-02-12 | GSE248391 | GEO

IL-9 is required for multi-cytokine producing tissue-resident memory CD4+ T cell-dependent allergic airway recall responses

Project description:Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses are not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we have characterized a sub-population of Th2 cells that secretes IL-9 as an obligate effector cytokine. IL-9-secreting cells have a resident memory T cell phenotype and blocking IL-9 during a recall challenge significantly diminishes airway inflammation and airway hyperreactivity. T cells secrete IL-9 in response to allergen recall and secretion is amplified by IL-33. Using scRNA-seq and scATAC-seq, we define the cellular identity of a distinct populations of T cells with pro-allergic cytokine patterns. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multi-cytokine producing cell population is required for an allergen recall response.

2022-01-31 | GSE190795 | GEO

Distinct roles of FOXA2 and FOXA3 in allergic airway disease

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

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Distinct roles of FOXA2 and FOXA3 in allergic airway disease

2010-04-03 | E-GEOD-13382 | biostudies-arrayexpress

Transcription profiling of mouse lung from individuals with airway hyperactivity and goblet cell metaplasia post-Sendai virus infection

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).

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Targeting mitochondrial reactive oxygen species alleviates allergic airway disease in a mouse model of obese allergic asthma

Project description:Obesity is associated with severe, difficult to control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment strategy. Using a mouse model of house dust mite (HDM) induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ); we investigated the effects of obesity and mROS on airway inflammation, remodelling and airway hyperreactivity (AHR). HDM induces airway inflammation, remodelling and hyperreactivity in both lean and obese mice. Obese allergic mice showed increased lung tissue eotaxin levels, airway tissue eosinophilia and AHR when compared to lean allergic mice. MitoQ reduced markers of airway inflammation, remodelling and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obeseHDM mice. mROS regulates cell signalling by protein oxidation of multiple downstream targets: MitoQ reduced HDM-induced cysteine-sulfenylation of several proteins including those involved in the unfolded protein response (UPR). In summary, mROS mediates the development of allergic airway disease and hence MitoQ might be effective for the treatment for asthma, and specific features of obese asthma.

2023-06-02 | PXD029715 | Pride

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