Pulmonary neuroendocrine cells amplify allergic asthma responses

Abstract

Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that -mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in-mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.

Neuroendocrine regulation of innate lymphoid cells

“…Mice lacking PNECs have smaller numbers of ILC2s, eosinophils, and Th2 cells after OVA challenge. In particular, ILC2s colocalize with PNECs near airway branch points, and express the receptors for both CGRP and GABA . However, whereas GABA has a negligible effect, CGRP increases IL‐5 production by ILC2s cultured with IL‐7, IL‐33, and IL‐25, and deletion of the CGRP receptor in ILCs in vivo results in lower levels of immune cell infiltration in HDM‐treated mice .…”

“…These findings suggest that the stimulation of efferent neurons may activate PNECs, which, when exposed to large quantities of airborne antigens, trigger lung immune cell activation via neuropeptide secretion . Indeed, PNECs amplify allergen‐induced type 2 immune responses in the mouse OVA‐ and HDM‐induced asthma models, and, in addition to neuropeptides, they also release GABA, which stimulates goblet cell hyperplasia …”

“…In another study, lung IL‐5‐producing ILC2s were found in collagen‐rich regions near the confluence of medium‐sized blood vessels and airways . More recently, IL‐5 + ILC2s were found to reside close to PNECs in the airway branch junctions (nodal points), where particles entering the airways tend to concentrate . ILC2s are, thus, strategically located within the airway mucosal tissue, so as to form signaling centers with the neuroendocrine system for patrolling the airways and potentially recruiting circulating immune cells to sites of damage or pathogen invasion.…”

“…Pulmonary neuroendocrine cells (PNECs) represent an important source of neuropeptides in addition to the sensory nerves innervating the lung. In OVA‐induced airway inflammation, they express CGRP, chromogranin A and neuropeptide Y, together with the neurotransmitter GABA . Mice lacking PNECs have smaller numbers of ILC2s, eosinophils, and Th2 cells after OVA challenge.…”

“…However, whereas GABA has a negligible effect, CGRP increases IL‐5 production by ILC2s cultured with IL‐7, IL‐33, and IL‐25, and deletion of the CGRP receptor in ILCs in vivo results in lower levels of immune cell infiltration in HDM‐treated mice . Consistent with these findings for mice, PNECs form larger clusters in the lungs of human asthma patients than in controls …”