Early life allergen‐induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion

Abstract

Pulmonary neuroendocrine cells (PNECs) are the only innervated airway epithelial cells. To what extent neural innervation regulates PNEC secretion and function is unknown. Here, we discover that neurotrophin 4 (NT4) plays an essential role in mucus overproduction after early life allergen exposure by orchestrating PNEC innervation and secretion of GABA. We found that PNECs were the only cellular source of GABA in airways. In addition, PNECs expressed NT4 as a target-derived mechanism underlying PNEC innervation during development. Early life allergen exposure elevated the level of NT4 and caused PNEC hyperinnervation and nodose neuron hyperactivity. Associated with aberrant PNEC innervation, the authors discovered that GABA hypersecretion was required for the induction of mucin Muc5ac expression. In contrast, mice were protected from allergen-induced mucus overproduction and changes along the nerve-PNEC axis without any defects in inflammation. Last, GABA installation restored mucus overproduction in mice after early life allergen exposure. Together, our findings provide the first evidence for NT4-dependent neural regulation of PNEC secretion of GABA in a neonatal disease model. Targeting the nerve-PNEC axis may be a valid treatment strategy for mucus overproduction in airway diseases, such as childhood asthma.-Barrios, J., Patel, K. R., Aven, L., Achey, R., Minns, M. S., Lee, Y., Trinkaus-Randall, V. E., Ai, X. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion.

Neurotrophins in Asthma

“…Mice deficient in BDNF had significant defects in branching axons and 50% reduction in ASM innervation density compared to WTcontrols [39]. BDNF expression has also been described in airway epithelium and immune cells, such as T cells, macrophages, and mast cells, while TrkB expression has been detected on CD45+ lymphocytes, mast cells, alveolar type II cells, and eosinophils [11, 40••, 41]. Notably, while others showed TrkB receptor in cultured human ASM cells [12], TrkB lineage tracing in mice found no evidence of TrkB expression in ASM cells.…”

“…Notably, while others showed TrkB receptor in cultured human ASM cells [12], TrkB lineage tracing in mice found no evidence of TrkB expression in ASM cells. The discrepancy may be caused by differences between species or by culture conditions [40••]. In the mouse model of allergic inflammation, BDNF levels were elevated in BALF and in activated macrophages [11].…”

“…These findings indicate that BDNF and NT4 play distinct roles that may be explained at least in part by the difference in temporal expression. NT4 was expressed by ASM, PNECs, and mast cells in postnatal lungs of mouse, nonhuman primates, and humans [40••, 57••, 58••] (Fig. 3).…”

“…3). NT4 is required for the innervation of the lung, as NT4 −/− mice have significantly less nerve density in ASM and selective reduction of PNEC innervation by purinergic nerves [40••, 57••]. …”

“…Therefore, elevated NT4 levels following early life allergen exposure likely through an indirect mode of action by causing airway dysfunction through aberrant neural innervation [58••]. Functional rescue assays in NT4 −/− mice identified that the hypercontractile phenotype of ASM is caused by cholinergic hyperinnervation, while deregulated neural control of GABA secretion from PNECs is involved in mucus overproduction following early life allergen exposure [40••, 59]. Consistent with the findings in the rodent model of early life allergen exposure, children with asthma have elevated serum levels of NT4 [56].…”