Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction

Yu, Wenjie; Moninger, Thomas O.; Rector, Michael V.; Stoltz, David A.; Welsh, Michael J.

doi:10.1016/j.devcel.2022.08.010

Cited by 14 publications

(16 citation statements)

References 89 publications

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“…In non-CF HBECs we found that succinate induced a negative change in I SC that was prevented when cells were pre-incubated with the CFTR inhibitor CFTR inh 172, but remained unaltered by TRPM5 or M3 inhibition (Figure 4A). These data indicate that succinate-induced anion secretion was CFTR-dependent but, importantly, that it was activated by a different signalling pathway than in mouse 25 . We further confirmed the involvement of CFTR by performing the same experiment in cells isolated from CF patients homozygous for the ΔF508-CFTR mutation, and no changes in I SC in response to succinate were observed in HBECs of this genotype (Figure 4A).…”

Section: Resultsmentioning

confidence: 78%

“…Unlike mice that express SUCNR1 in brush cells, humans express the SUCNR1 in a different type of airway cell, the pulmonary neuroendocrine cell (PNEC) 25 , a rare cell type that participates in the heightened response to allergens in asthmatic patients 26 . In addition, succinate is increased in the bronchoalveolar lavage of CF patients, favouring Pseudomonas aeruginosa colonization 27 .…”

Section: Introductionmentioning

confidence: 99%

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Airway succinate chemosensing induces CFTR-dependent anion secretion and mucus clearance which is impaired in cystic fibrosis

Apablaza,

Barros-Poblete,

Delpiano

et al. 2024

Preprint

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The respiratory tract possesses a highly regulated innate defense system which includes efficient cilia-mediated mucus transport or mucociliary clearance (MCC). This essential process relies on appropriate hydration of airway surfaces which is controlled by a blend of transepithelial sodium and liquid absorption via the epithelial sodium channel (ENaC), and anion and liquid secretion, primarily regulated by the cystic fibrosis transmembrane conductance regulator (CFTR) channel. MCC is tightly regulated by second messenger signalling pathways. Succinate is derived from parasites, microorganisms and inflammatory cells, and its concentration increases in the airway surface liquid (ASL) during infections. Increases in ASL succinate activates the G-protein coupled succinate receptor (SUCNR1), which acts as a succinate sensor. Here, we tested the hypothesis that succinate signalling was linked to CFTR activity, ASL hydration and increased MCC. We observed that SUCNR1 activation stimulated anion secretion, increased mucus transport and induced bronchoconstriction in mouse airways. In parallel, stimulation of human bronchial epithelial cells (HBEC) with succinate activated anion secretion and increased ASL height. All functions activated by succinate/SUCNR1 were impeded when working with tissues and cells isolated from animal models or individuals affected cystic fibrosis (CF) or when CFTR was inhibited. Moreover, when HBECs derived from ΔF508 individuals were incubated with the triple drug combination of elexacaftor/tezacaftor/ivacaftor (ETI), succinate-induced anion secretion was restored, confirming the tight relationship between SUCNR1 signalling and CFTR function. Our results identify a novel activation pathway for CFTR that participates in the defence response of the airways, which is defective in CF. We propose that succinate acts as a danger molecule that alerts the airways to the presence of pathogens leading to a flushing out of the airways.

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Section: Resultsmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Airway succinate chemosensing induces CFTR-dependent anion secretion and mucus clearance which is impaired in cystic fibrosis

Apablaza,

Barros-Poblete,

Delpiano

et al. 2024

Preprint

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“…Neurons expressing P2RX2 and/or P2RX3 purinergic receptors densely innervate the trachea and larynx and reside in close proximity to tracheal NE cells ( 51 ). Furthermore, immortalized human small cell lung cancer lines have been shown to release adenosine 5′-triphosphate (ATP) into the culture medium ( 27 ). To determine whether NE cell stimulation evokes time-locked ATP release, we positioned a biosensor cell expressing the ATP1.0 biosensor ( 52 ) next to a dissociated NE cell.…”

Section: Tracheal and Laryngeal Ne Cells Communicate With Neurons Thr...mentioning

confidence: 99%

“…Pulmonary NE cells, a subtype that resides in the intrapulmonary airways, also have important roles in type 2 immune responses (16)(17)(18)(19) and small cell lung cancer (20,21). Although pulmonary NE cells may detect multimodal stimuli (22)(23)(24)(25)(26)(27)(28), their functional properties are relatively unknown compared with those of sensory epithelial cells in other organs. Even less is known about the sensory properties and functions of NE cells in more proximal airways, such as the trachea and larynx.…”

mentioning

confidence: 99%

Neuroendocrine cells initiate protective upper airway reflexes

Seeholzer,

Julius

2024

Science

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Airway neuroendocrine (NE) cells have been proposed to serve as specialized sensory epithelial cells that modulate respiratory behavior by communicating with nearby nerve endings. However, their functional properties and physiological roles in the healthy lung, trachea, and larynx remain largely unknown. In this work, we show that murine NE cells in these compartments have distinct biophysical properties but share sensitivity to two commonly aspirated noxious stimuli, water and acid. Moreover, we found that tracheal and laryngeal NE cells protect the airways by releasing adenosine 5′-triphosphate (ATP) to activate purinoreceptive sensory neurons that initiate swallowing and expiratory reflexes. Our work uncovers the broad molecular and biophysical diversity of NE cells across the airways and reveals mechanisms by which these specialized excitable cells serve as sentinels for activating protective responses.

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“…We then hypothesized that those physiological functions that are normally ascribed to mature tuft cells, such as environmental sensing, may be assumed by other cell types in the steady state human airway epithelium. Supporting this hypothesis, genes related to bitter taste receptors ( TAS2R4 , TAS2R43 ) are expressed by human ciliated cells 29 , genes related to olfactory receptor-mediated functions are expressed in NE 30 cells and genes for succinate sensing ( e.g ., succinate receptor ( SUCNR1 )) are expressed in glandular NE cells 31 . Indeed, NE cells from our deep cell atlas and human LAE cultures expressed the succinate receptor ( SUCNR1 ), whereas POU2F3 + “tuft-like” cells did not ( Extended Data Fig.…”

Section: Mainmentioning

confidence: 99%

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

Waghray,

Monga,

Lin

et al. 2023

Preprint

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The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma-associated alarmins. However, surprisingly, exceedingly few mature tuft cells have been identified in human lung cell atlases despite the ready identification of rare ionocytes and neuroendocrine cells. To identify human rare cell progenitors and define their lineage relationship to mature tuft cells, we generated a deep lung cell atlas containing 311,748 single cell RNA-Seq (scRNA-seq) profiles from discrete anatomic sites along the large and small airways and lung lobes of explanted donor lungs that could not be used for organ transplantation. Of 154,222 airway epithelial cells, we identified 687 ionocytes (0.45%) that are present in similar proportions in both large and small airways, suggesting that they may contribute to both large and small airways pathologies in CF. In stark contrast, we recovered only 3 mature tuft cells (0.002%). Instead, we identified rare bipotent progenitor cells that can give rise to both ionocytes and tuft cells, which we termed tuft-ionocyte progenitor cells (TIP cells). Remarkably, the cycling fraction of these TIP cells was comparable to that of basal stem cells. We used scRNA-seq and scATAC-seq to predict transcription factors that mark this novel rare cell progenitor population and define intermediate states during TIP cell lineage transitions en route to the differentiation of mature ionocytes and tuft cells. The default lineage of TIP cell descendants is skewed towards ionocytes, explaining the paucity of mature tuft cells in the human airway. However, Type 2 and Type 17 cytokines, associated with asthma and CF, diverted the lineage of TIP cell descendantsin vitro, resulting in the differentiation of mature tuft cells at the expense of ionocytes. Consistent with this model of mature tuft cell differentiation, we identify mature tuft cells in a patient who died from an asthma flare. Overall, our findings suggest that the immune signaling pathways active in asthma and CF may skew the composition of disease-relevant rare cells and illustrate how deep atlases are required for identifying physiologically-relevant scarce cell populations.

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Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction

Cited by 14 publications

References 89 publications

Airway succinate chemosensing induces CFTR-dependent anion secretion and mucus clearance which is impaired in cystic fibrosis

Airway succinate chemosensing induces CFTR-dependent anion secretion and mucus clearance which is impaired in cystic fibrosis

Neuroendocrine cells initiate protective upper airway reflexes

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

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