An Airway Protection Program Revealed by Sweeping Genetic Control of Vagal Afferents

Prescott, Sara L.; Umans, Benjamin D.; Williams, Eric; Brust, Rachael D.; Liberles, Stephen D.

doi:10.1016/j.cell.2020.03.004

Cited by 120 publications

(185 citation statements)

References 72 publications

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“…We investigated P2X 2 -expressing terminals in the trachea and esophagus, which are likely projected from nodose neurons (Ricco et al, 1996;Yu et al, 2005;Kwong et al, 2008;Prescott et al, 2020). Previous studies of vagal afferent terminations in the mouse trachea using GFP expression following intraganglionic injections of an AAV-GFP construct have identified two classes of vagal afferents in the membranous area of the trachea: dorsal terminal structures that had fibers running largely in parallel to the smooth muscle but did not penetrate the epithelial layer, and small intraepithelial terminals (Hennel et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Development of a Mouse Reporter Strain for the Purinergic P2X₂Receptor

Kim

Bahia

Patil

et al. 2020

eNeuro

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The ATP-sensitive P2X 2 ionotropic receptor plays a critical role in a number of signal processes including taste and hearing, carotid body detection of hypoxia, the exercise pressor reflex and sensory transduction of mechanical stimuli in the airways and bladder. Elucidation of the role of P2X 2 has been hindered by the lack of selective tools. In particular, detection of P2X 2 using established pharmacological and biochemical techniques yields dramatically different expression patterns, particularly in the peripheral and central nervous systems. Here, we have developed a knockin P2X 2-cre mouse, which we crossed with a cre-sensitive tdTomato reporter mouse to determine P2X 2 expression. P2X 2 was found in more than 80% of nodose vagal afferent neurons, but not in jugular vagal afferent neurons. Reporter expression correlated in vagal neurons with sensitivity to mATP. P2X 2 was expressed in 75% of petrosal afferents, but only 12% and 4% of dorsal root ganglia and trigeminal afferents, respectively. P2X 2 expression was limited to very few cell types systemically. Together with the central terminals of P2X 2expressing afferents, reporter expression in the CNS was mainly found in brainstem neurons projecting mossy fibers to the cerebellum, with little expression in the hippocampus or cortex. The structure of peripheral terminals of P2X 2-expressing afferents was demonstrated in the tongue (taste buds), carotid body, trachea and esophagus. P2X 2 was observed in hair cells and support cells in the cochlear, but not in spiral afferent neurons. This mouse strain provides a novel approach to the identification and manipulation of P2X 2-expressing cell types. 3 Significance statement Inhibitor and knockout studies have demonstrated the critical role of P2X 2 in multiple sensory signaling pathways. Nevertheless, P2X 2 expression patterns are controversial, as biochemical studies suggest widespread expression whereas functional studies suggest restricted expression. Functional characterization is further complicated by heteromeric P2X 2/3 channels that have hybrid pharmacology and biophysical properties. We have developed a P2X 2-cre mouse to determine the expression pattern of P2X 2. In the periphery, P2X 2 expression is found in almost all nodose sensory afferents but is limited to only minor subsets of trigeminal and DRG afferents. Centrally, P2X 2 is mostly expressed in neurons projecting mossy fibers to the cerebellum. Thus we provide novel evidence for the specific expression of P2X 2 , which is more limited than previously thought.

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Section: Discussionmentioning

confidence: 99%

Development of a Mouse Reporter Strain for the Purinergic P2X₂Receptor

Kim

Bahia

Patil

et al. 2020

eNeuro

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“…A recently discovered class of vagal throat-innervating P2RY1 + neurons has been shown to be involved in protective reflexes elicited by various airway irritants 54 . Although their precise mechanism of action remains elusive, these sensory neurons seem to detect cell mechanical responses mediated by airway stretch receptors such as Piezo2 and initiate defensive reflexes that ensure airway integrity 55 .…”

Section: Lung Innervation and Immunitymentioning

confidence: 99%

Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19

Virgiliis

Giovanni

2020

Nat Rev Neurol

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COVID-19 is an infectious disease caused by the coronavirus SARS-CoV-2, which was first reported in Wuhan, China, in December 2019 and has caused a global pandemic. Acute respiratory distress syndrome (ARDS) is a common feature of severe forms of COVID-19 and can lead to respiratory failure, especially in older individuals. The increasing recognition of the neurotropic potential of SARS-CoV-2 has sparked interest in the role of the nervous system in respiratory failure in people with COVID-19. However, the neuroimmune interactions in the lung in the context of ARDS are poorly understood. In this Perspectives article, we propose the concept of the neuroimmune unit as a critical determinant of lung function in the context of COVID-19, inflammatory conditions and ageing, focusing particularly on the involvement of the vagus nerve. We discuss approaches such as neurostimulation and pharmacological neuromodulation to reduce tissue inflammation with the aim of preventing respiratory failure.

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“…Recently, it has been demonstrated that ATP through P2Y1 receptor activation on airway vagal sensory neurons activates protective reflexes of the upper airways, like reflexes to avoid pulmonary aspiration, such as pharyngeal swallowing. A hyperstimulation of this neuronal circuits may contribute to airway diseases, such as asthma and COPD (Prescott et al, 2020). Further work will be necessary for a complete investigation of the control of the ATP/ADP/adenosine balance in airways.…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Allergic Airway Inflammation in Mice Lacking ECTO-5′-Nucleotidase (CD73)

et al. 2020

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The airways are a target tissue of type I allergies and atopy is the main etiological factor of bronchial asthma. A predisposition to allergy and individual response to allergens are dependent upon environmental and host factors. Early studies performed to clarify the role of extracellular adenosine in the airways highlighted the importance of adenosine-generating enzymes CD73, together with CD39, as an innate protection system against lung injury. In experimental animals, deletion of CD73 has been associated with immune and autoimmune diseases. Our experiments have been performed to investigate the role of CD73 in the assessment of allergic airway inflammation following sensitization. We found that in CD73−/− mice sensitization, induced by subcutaneous ovalbumin (OVA) administration, increased signs of airway inflammation and atopy developed, characterized by high IgE plasma levels and increased pulmonary cytokines, reduced frequency of lung CD4+CD25+Foxp3+ T cells, but without bronchial hyperreactivity, compared to sensitized wild type mice. Our results provide evidence that the lack of CD73 causes an uncontrolled allergic sensitization, suggesting that CD73 is a key molecule at the interface between innate and adaptive immune response. The knowledge of host immune factors controlling allergic sensitization is of crucial importance and might help to find preventive interventions that could act before an allergy develops.

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An Airway Protection Program Revealed by Sweeping Genetic Control of Vagal Afferents

Cited by 120 publications

References 72 publications

Development of a Mouse Reporter Strain for the Purinergic P2X₂Receptor

Development of a Mouse Reporter Strain for the Purinergic P2X₂Receptor

Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19

Exacerbation of Allergic Airway Inflammation in Mice Lacking ECTO-5′-Nucleotidase (CD73)

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An Airway Protection Program Revealed by Sweeping Genetic Control of Vagal Afferents

Cited by 120 publications

References 72 publications

Development of a Mouse Reporter Strain for the Purinergic P2X2Receptor

Development of a Mouse Reporter Strain for the Purinergic P2X2Receptor

Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19

Exacerbation of Allergic Airway Inflammation in Mice Lacking ECTO-5′-Nucleotidase (CD73)

Contact Info

Product

Resources

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Development of a Mouse Reporter Strain for the Purinergic P2X₂Receptor

Development of a Mouse Reporter Strain for the Purinergic P2X₂Receptor