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• W2803792330 abstract "Organisms have developed cellular “antennas” to sense, interpret, and integrate environmental stimuli. In a recent issue of Science, Sui et al., 2018Sui P. Wiesner D.L. Xu J. Zhang Y. Lee J. Van Dyken S. Lashua A. Yu C. Klein B.S. Locksley R.M. et al.Pulmonary neuroendocrine cells amplify allergic asthma responses.Science. 2018; (Published online March 29, 2018): eaan8546https://doi.org/10.1126/science.aan8546Crossref PubMed Scopus (192) Google Scholar 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. Organisms have developed cellular “antennas” to sense, interpret, and integrate environmental stimuli. In a recent issue of Science, Sui et al., 2018Sui P. Wiesner D.L. Xu J. Zhang Y. Lee J. Van Dyken S. Lashua A. Yu C. Klein B.S. Locksley R.M. et al.Pulmonary neuroendocrine cells amplify allergic asthma responses.Science. 2018; (Published online March 29, 2018): eaan8546https://doi.org/10.1126/science.aan8546Crossref PubMed Scopus (192) Google Scholar 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 chemicals 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., 2017Hockman D. Burns A.J. Schlosser G. Gates K.P. Jevans B. Mongera A. Fisher S. Unlu G. Knapik E.W. Kaufman C.K. et al.Evolution of the hypoxia-sensitive cells involved in amniote respiratory reflexes.Elife. 2017; 6: e21231Crossref PubMed Scopus (39) Google Scholar). 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., 2018Sui P. Wiesner D.L. Xu J. Zhang Y. Lee J. Van Dyken S. Lashua A. Yu C. Klein B.S. Locksley R.M. et al.Pulmonary neuroendocrine cells amplify allergic asthma responses.Science. 2018; (Published online March 29, 2018): eaan8546https://doi.org/10.1126/science.aan8546Crossref PubMed Scopus (192) Google Scholar 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 developmentally derived from endodermal progenitors. PNECs are marked by calcitonin 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 pulmonary neuroendocrine bodies (PNEBs) (Branchfield et al., 2016Branchfield K. Nantie L. Verheyden J.M. Sui P. Wienhold M.D. Sun X. Pulmonary neuroendocrine cells function as airway sensors to control lung immune response.Science. 2016; 351: 707-710Crossref PubMed Scopus (130) Google Scholar, Kuo and Krasnow, 2015Kuo C.S. Krasnow M.A. Formation of a neurosensory organ by epithelial cell slithering.Cell. 2015; 163: 394-405Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, Noguchi et al., 2015Noguchi M. Sumiyama K. Morimoto M. Directed migration of pulmonary neuroendocrine cells toward airway branches organizes the stereotypic location of neuroepithelial bodies.Cell Rep. 2015; 13: 2679-2686Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). 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., 2007Cutz E. Perrin D.G. Pan J. Haas E.A. Krous H.F. Pulmonary neuroendocrine cells and neuroepithelial bodies in sudden infant death syndrome: potential markers of airway chemoreceptor dysfunction.Pediatr. Dev. Pathol. 2007; 10: 106-116Crossref PubMed Scopus (37) Google Scholar, Gu et al., 2014Gu X. Karp P.H. Brody S.L. Pierce R.A. Welsh M.J. Holtzman M.J. Ben-Shahar Y. Chemosensory functions for pulmonary neuroendocrine cells.Am. J. Respir. Cell Mol. Biol. 2014; 50: 637-646Crossref PubMed Scopus (94) Google Scholar), implying that PNECs may regulate inflammatory 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., 2018Sui P. Wiesner D.L. Xu J. Zhang Y. Lee J. Van Dyken S. Lashua A. Yu C. Klein B.S. Locksley R.M. et al.Pulmonary neuroendocrine cells amplify allergic asthma responses.Science. 2018; (Published online March 29, 2018): eaan8546https://doi.org/10.1126/science.aan8546Crossref PubMed Scopus (192) Google Scholar). 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 innervation or the numbers of immune cells in the lung. Because PNECs were previously thought to act as sensors of environmental stimuli, the authors exposed PNEC-depleted mice to aerosolized ovalbumin (OVA), a widely used experimental asthma model that is known to induce inflammation and hyperplasia of mucus-secreting goblet cells in the airway. Interestingly, 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) exposure, 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 neurotransmitters 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 contributes to allergic responses, the authors used a conditional loss of GABA production (Gad1 loss) or transport (Vgat loss) in lung epithelial cells. They found a significant decrease in goblet cell hyperplasia in both mutants following allergen exposure. Interestingly, this was achieved without any change in ILC2 number, and their activation in both mutants and GABA was unable to activate ILC2s in ex vivo cultures. These data imply that GABA from PNECs is necessary for goblet cell hyperplasia, but not for ILC2 stimulation (Figure 1). This finding raises the question of whether CGRP is the sole neuropeptide responsible for stimulation of ILC2s after allergen exposure. Indeed, two other recent studies, using single-cell RNA-seq analysis, identified increased levels of Neuromedin U (NMU) receptor expression in ILC2s after allergen exposure (Klose et al., 2017Klose C.S.N. Mahlakõiv T. Moeller J.B. Rankin L.C. Flamar A.-L. Kabata H. Monticelli L.A. Moriyama S. Putzel G.G. Rakhilin N. et al.The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.Nature. 2017; 549: 282-286Crossref PubMed Scopus (320) Google Scholar, Wallrapp et al., 2017Wallrapp A. Riesenfeld S.J. Burkett P.R. Abdulnour R.-E.E. Nyman J. Dionne D. Hofree M. Cuoco M.S. Rodman C. Farouq D. et al.The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation.Nature. 2017; 549: 351-356Crossref PubMed Scopus (365) Google Scholar). Although the source of NMU was not from PNECs, the loss of NMU receptor in ILC2s significantly abrogated allergen-induced inflammatory response, indicating that multiple peptides/molecules are able to stimulate ILC2s. Neuro-immunomodulatory functions of PNECs make them a potential target for future therapies. However, many outstanding questions remain. For example, how do PNECs sense or detect airborne allergens and other particles? Additionally, do PNECs distinguish between different forms of stimulants (i.e., protein, DNA, particulate, or other chemicals)? And if so, how? It is also not clear how PNECs functionally regenerate following severe airway damage. Additionally, there are fewer PNEC clusters in human airways compared to rodents. This raises the question of whether single and clustered PNECs are functionally distinct and heterogeneous. Given their dysregulation in asthmatic and other airway diseases, understanding and harnessing the full potential of PNECs may provide new therapeutic avenues to prevent and treat inflammation-associated airway diseases." @default.
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• W2803792330 title "Pulmonary Neuroendocrine Cells: Sensors and Sentinels of the Lung" @default.
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