Pulmonary neuroendocrine cells function as airway sensors to control lung immune response

Abstract

The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Here, we show that Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population. Robo inactivation in mouse lung results in an inability of PNECs to cluster into sensory organoids and triggers increased neuropeptide production upon exposure to air. Excess neuropeptides lead to an increase in immune infiltrates, which in turn remodel the matrix and irreversibly simplify the alveoli. We demonstrate in vivo that PNECs act as precise airway sensors that elicit immune responses via neuropeptides. These findings suggest that the PNEC and neuropeptide abnormalities documented in a wide array of pulmonary diseases may profoundly affect symptoms and progression.

PBX transcription factors drive pulmonary vascular adaptation to birth

“…Three mice from each group were analyzed, with three images taken from sections of the apex, middle, and base of the lungs of each mouse. The MLI was calculated as previously described using a 12 × 8, 50-μm grid (56). The average MLI was calculated for each mouse and then averaged within each group.…”

Plasticity in the lung: making and breaking cell identity

“…PNECs of the bronchiolar epithelium are also thought to serve as niche cells for naphthalene-resistant variant club cells (Guha et al, 2012;Hong et al, 2001). Several studies have suggested that PNECs perform many other functions including oxygen sensing, mechanotransduction, immune cell recruitment, and chemosensing (Branchfield et al, 2016;Lembrechts et al, 2012;Pan et al, 2002). Some of these functions are presumably mediated in part through their connections with nerve fibers.…”

“…In addition to the roles described above, these major epithelial cell types are likely to possess other functions at steady state and after injury. Indeed, less frequent cell types, such as M cells and brush cells are already known to exist, and even their physiological functions are still being interrogated (Branchfield et al, 2016;Krasteva et al, 2012;Reid et al, 2005;Song et al, 2012;Teitelbaum et al, 1999). In some of the aforementioned functional cell types, such as secretory cells or type 2 cells, subsets of cells are thought to possess differing progenitor cell activities even under steady state conditions Guha et al, 2014;Reynolds et al, 2002) and much more is likely to be learned about this in the coming decade.…”

Epithelial cell behaviours during neurosensory organ formation

“…What signals underlie directionality and promote the integration of additional NE cells into a NEB? One possible mechanism is through the roundabout receptor (Robo), which is expressed in NEB cells: abrogation of its activity results in non-clustered, dispersed NE cells in the lung epithelium (Branchfield et al, 2016). However, further studies are clearly needed to answer these questions and gain a better understanding of this mode of epithelial cell motility.…”

“…4A) (Cutz et al, 2013). In pathological conditions, their unclustering is associated with increased neuropeptide release and increased immune response (Branchfield et al, 2016). Whereas single cells and small clusters are randomly scattered throughout the bronchial epithelium, large groups, referred to as NEBs, are located in a stereotyped pattern at the branchpoints of the mammalian secondary airway (which excludes the trachea and primary bronchi).…”