Pulmonary neuroendocrine cells secrete γ-aminobutyric acid to induce goblet cell hyperplasia in primate models

Juliana Barrios, Alvin T. Kho, Linh Aven, Jennifer A. Mitchel, Jin Ah Park, Scott H. Randell, Lisa Miller, Kelan G. Tantisira, Xingbin Ai

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Mucus overproduction is a major contributor to morbidity and mortality in asthma. Mucus overproduction is induced by orchestrated actions of multiple factors that include inflammatory cytokines and γ-aminobutyric acid (GABA).GABAis produced only by pulmonary neuroendocrine cells (PNECs) in the mouse lung. Recent studies in a neonatal mouse model of allergic inflammation have shown that PNECs play an essential role in mucus overproduction by GABA hypersecretion. Whether PNECs mediate dysregulatedGABAsignaling for mucus overproduction in asthma is unknown. In this study, we characterized the cellular source ofGABA in the lungs of nonhuman primates and humans and assessed GABA secretion and signaling in primate disease models.Wefound that like in mice, PNECs were the major source of GABA in primate lungs. In addition, an infant nonhuman primate model of asthma exhibited an increase in GABA secretion. Furthermore, subjects with asthma had elevated levels of expression of a subset of GABA type a (GABAa) and type b (GABAb) receptors in airway epithelium compared with those of healthy control subjects. Last, employing a normal human bronchial epithelial cell model of preinduced mucus overproduction, we showed pharmaceutical blockade of GABAa and GABAb receptor signaling reversed the effect of IL-13 on MUC5AC gene expression and goblet cell proliferation. Together, our data demonstrate an evolutionarily conserved intraepithelial GABA signaling that, in concert with IL-13, plays an essential role in mucus overproduction. Our findings may offer new strategies to ameliorate mucus overproduction in patients with asthma by targeting PNEC secretion and GABA signaling.

Original languageEnglish (US)
Pages (from-to)687-694
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume60
Issue number6
DOIs
StatePublished - Jun 1 2019

Keywords

  • Asthma
  • Goblet cell hyperplasia
  • Mucus overproduction
  • Pulmonary neuroendocrine cell
  • γ-aminobutyric acid

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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