Rare innervated lung epithelial cells act as air sensors and regulate lung inflammation

November 08, 2016

The lungs are constantly exposed to numerous environmental stimuli. How are these stimuli being
sensed and how the response is generated is poorly understood.

A recent study published in Science has described a novel neuroendocrine pathway regulating the
development of lung inflammation, involving a rare, innervated epithelial cell population in the lungs.

Branchfield et al. demonstrate that these cells, known as pulmonary neuroendocrine cells (PNECs),
function as airway sensors – they are able to receive, interpret and respond to different
environmental stimuli, such as allergens or chemicals in the air we breathe.

PNECs are the only innervated cells in the airway epithelium and make up less than 1 % of all airway
epithelial cells. Their main function is to, in response to fluctuations in oxygen levels, release
bioactive neuropeptides, such as 5‐hydroxytryptamine (serotonin) and calcitonin gene‐related
peptide (CGRP). In mouse lungs, they have been shown to form highly innervated clusters, known as
neuroepithelial bodies (NEBs). Alterations in PNECs numbers have been associated with numerous
human lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma
and congenital diaphragmatic hernia (CDH).

The initial goal of the study was to understand what the underlying cause of CDH disease is. This is a
rather common birth defect where organs from the abdomen move to the chest due to a hole in a
diaphragm, the muscle controlling breathing. The survivors often experience symptoms similar to
pulmonary hypertension or asthma. Human CDH has been associated with mutations in Roundabout
receptor genes (ROBO) coding for membrane proteins, ROBO1 and ROBO2. Using a genetic mouse
model of CDH, where Robo1 and Robo2 were knocked out in the endoderm‐derived epithelium
(including the lung epithelium), authors were able to mimic CDH. Animals suffered from alveolar
simplification (reduction in the gas‐exchange surface), upregulation of genes coding for important
inflammatory mediators (cytokines and chemokines), together with increased number of different
immune cells including neutrophils, eosinophils, macrophages and T cells in the lungs. Unexpectedly,
further analysis showed that that these animals have a failure in PNECs clustering – PNECs stay as
solitary cells. In addition, PNECs were the only Robo‐expressing cells in the lung epithelium,
suggesting that expression of Robo is necessary for their clustering. As solitary cells are more
sensitive to environmental cues, this could explain the inflammatory phenotype and alveolar
simplification in the absence of Robo expression.

To further understand how exactly PNECs regulate these responses the authors examined their
neuropeptide production. In the absence of Robo, several neuropeptides, in particular CGRP, were
upregulated in the lungs. Importantly, they could show that upregulation of neuropeptides is a
consequence of unclustering of PNECs. Phenotype of Robo‐Cgrp double knockout animals was milder
than of Robo mutants, with less simplified alveoli and reduction in lung immune cell numbers. These
findings confirmed that alveolar simplification and infiltration of immune cells is a consequence of
dysfunctional unclustered PNECs due to the absence of ROBO1 and ROBO2 membrane proteins.
This study underlines the importance of PNECs as main pulmonary sensors that detect environmental
cues in the air and send gathered “information” to the central nervous system, where signals are
processed and sent back to PNECs which accordingly modify their neuropeptide production.
Interestingly, it appears that cluster formation is necessary to generate an appropriate neuropeptide
response, as solitary cells appear to be too sensitive and exhibit overreactive behavior leading to lung
inflammation. Disorders of the immune system, such as asthma, can be associated with an increase
in neuropeptide production. Therefore, demonstrating that PNECs have an important role in
regulating the lung immune response through neuropeptides, suggests that it may be possible to
modify their behavior for therapeutic purposes.

Masa Ivin

Branchfield, K. et al. Pulmonary neuroendocrine cells function as airway sensors to control lung
immune response, Science, 2016