Developmental Cell

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Pulmonary Neuroendocrine Cells:

Sensors and Sentinels of the Lung
Yoshihiko Kobayashi1 and Purushothama Rao Tata1,2,3,*
1Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
2Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
3Regeneration Next, Duke University, Durham, NC 27710, USA

*Correspondence: purushothamarao.tata@duke.edu
https://doi.org/10.1016/j.devcel.2018.05.009

Organisms have developed cellular ‘‘antennas’’ to sense, interpret, and integrate environmental stimuli. In a
recent issue of Science, Sui et al. (2018) demonstrate that discrete clusters of pulmonary neuroendocrine
cells in the lung can sense airborne allergens and relay signals to stimulate immune cells and induce
tissue/organ-wide responses.

During evolution, organisms have
constantly acquired, adapted, and
improved cellular systems to sense
and respond to chemical, mechanical,
and other environmental stimuli. For
example, unicellular bacteria have evolved
mechanisms to sense gradients of chemi-
cals such as antibiotics and nutrients
to coordinate metabolic activities with
neighboring cells and organisms for their
survival, growth, and predation. Among
multicellular organisms, some have
evolved specialized sensory cell types
called neuroepithelial sensors—also called
neuroendocrine cells (NECs)—which, as
their name implies, possess characteristics
of both neurons and hormone-secreting
endocrine cells. In vertebrates, NECs are
relatively rare but occur in multiple tissues
(Hockman et al., 2017). They have been
implicated in sensing taste, touch, odor,
and mechanical signals and are known to
control inflammation. However, the precise
mechanisms through which NECs regulate
these processes are unclear. In a recent
issue of Science, Sui et al., (2018) used
animal models of allergen exposure and
uncovered that pulmonary NECs (PNECs)
can sense airborne signals and induce
tissue-wide responses either directly or
indirectly through recruitment of ILC2 cells.
NECs constitute <1% of the total airway
epithelial cells in the lung and are devel-
opmentally derived from endodermal
progenitors. PNECs are marked by calci-
tonin gene-related peptide (CGRP) and
other neurotransmitter proteins. Several
recent studies showed that ROBO/SLIT
signaling recruits and organizes individual
NECs into discrete clusters called pul-
monary neuroendocrine bodies (PNEBs)
(Branchfield et al., 2016; Kuo and Kras-
now, 2015; Noguchi et al., 2015). These
often occur in clusters at highly innervated
airway branch points and form contacts
with nerve terminals (Figure 1). Some
rare individual NECs are also found
dispersed throughout the epithelium.
Interestingly, the numbers of PNECs are
significantly elevated in lung diseases,
including chronic obstructive pulmonary
disease (COPD) and sudden infant
death syndrome (SIDS), which are often
associated with chronic inflammation
(Cutz et al., 2007; Gu et al., 2014),
implying that PNECs may regulate inflam-
matory responses in both genetic and
environmental alterations.
To study the role of PNECs in the lung,
Sui et al. used Shh-promoter-driven Cre
to delete Ascl1, a transcription factor
gene that is specifically expressed in
PNECs, but not in other airway epithelial
cells (Sui et al., 2018). These mice develop
normally, but loss of Ascl1 in the lung
completely abrogated the specification
of PNECs. Interestingly, loss of PNECs
does not seem to influence airway inner-
vation or the numbers of immune cells
in the lung. Because PNECs were previ-
ously thought to act as sensors of envi-
ronmental stimuli, the authors exposed
PNEC-depleted mice to aerosolized oval-
bumin (OVA), a widely used experimental
asthma model that is known to induce
inflammation and hyperplasia of mucus-
secreting goblet cells in the airway. Inter-
estingly, PNEC-depleted mice developed
fewer goblet cells compared to controls.
In addition, PNEC depletion reduced the
number of group 2 innate lymphoid cells
(ILC2), which are known to be recruited
to the lung following allergen exposure.
The authors found a similar phenotype
following house dust mite (HDM) expo-
sure, another widely used lung exposure
model, suggesting that PNECs may play
a similar role in regulating responses to
allergen exposure.
The authors next asked how PNECs
regulate goblet cell hyperplasia and ILC2
recruitment, and whether this regulation
is direct or indirect. To address these
questions, the authors measured the
production of peptides and neurotrans-
mitters known to be secreted by PNECs.
Although they found a significant increase
in Calca (which encodes CGRP), Chga,
Npy, and Vip, as well as levels of
GABA after allergen exposure in wild-
type mice, that increase was significantly
diminished in mice lacking PNECs. These
data suggest that PNECs are necessary
for allergen-induced responses.
The authors went on to find that ILC2
cells are located in close proximity
to CGRP-expressing PNECs, suggesting
that PNEC-derived CGRPs directly act
on immune cells. To functionally test a
potential interaction between these two
cell types mediated through CGRP, the
authors used both in vivo (ILC2-specific
loss of CGRP receptor) and ex vivo (co-
culture of PNECs and ILC2s) models and
found that CGRP derived from PNECs
can directly act on ILC2s and promote
their activation and maturation, which
then further elicits other immunological
cascades through the cytokine IL5. To
functionally test whether GABA contrib-
utes to allergic responses, the authors
used a conditional loss of GABA produc-
tion (Gad1 loss) or transport (Vgat loss)

Developmental Cell 45, May 21, 2018 ª 2018 Elsevier Inc. 425
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fewer PNEC clusters in human airways

compared to rodents. This raises the ques-
tion of whether single and clustered PNECs
are functionally distinct and heteroge-
neous. Given their dysregulation in asth-
matic and other airway diseases, under-
standing and harnessing the full potential
of PNECs may provide new therapeutic
avenues to prevent and treat inflamma-
tion-associated airway diseases.

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Figure 1. Pulmonary Neuroendocrine Cells Detect Environmental Stimuli and Elicit Tissue-
wide Responses Hockman, D., Burns, A.J., Schlosser, G., Gates,
K.P., Jevans, B., Mongera, A., Fisher, S., Unlu,
(A) Schematic of the localization of neuroendocrine cells at the airway branch points. (B) Neuroendocrine
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