Pulmonary neuroendocrine cells amplify allergic asthma responses

Science. 2018 Jun 8;360(6393):eaan8546. doi: 10.1126/science.aan8546. Epub 2018 Mar 29.

Abstract

Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1-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 Ascl1-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / immunology*
  • Asthma / pathology*
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Calcitonin Gene-Related Peptide / metabolism
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology
  • Female
  • Goblet Cells / pathology
  • Humans
  • Hyperplasia
  • Lung / pathology*
  • Mice
  • Neuroendocrine Cells / immunology*
  • Neuroendocrine Cells / pathology*
  • gamma-Aminobutyric Acid / biosynthesis
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cytokines
  • gamma-Aminobutyric Acid
  • Calcitonin Gene-Related Peptide