Interleukin-13 Stimulation Reveals the Cellular and Functional Plasticity of the Airway Epithelium

Ann Am Thorac Soc. 2018 Apr;15(Suppl 2):S98-S102. doi: 10.1513/AnnalsATS.201711-868MG.

Abstract

About 50% of patients with asthma exhibit chronic airway inflammation driven by the type 2 cytokines interleukin (IL)-4, IL-5, and IL-13. These patients with type 2-high asthma experience more allergic symptoms, greater airway hyperresponsiveness, and more severe mucus obstruction than patients with type 2-low asthma. Mouse models of asthma have shown that much of the airway dysfunction in these models can be generated by IL-13 stimulation of the airway epithelium alone. Both in vivo mouse model studies and in vitro studies of human mucociliary airway epithelial cultures have shown that IL-13 induces cellular remodeling of the airway epithelium through proliferation-independent transdifferentiation processes. In both humans and mice, IL-13 stimulation of the airway epithelium results in generation of hypersecretory mucin 5AC (MUC5AC)-expressing mucus cells. Whereas club cells have been shown to be the source of these mucin 5AC-positive mucus cells in mice, the origin of these mucus cells in humans is unclear. In humans, chronic IL-13 stimulation appears to result in loss of ciliated cells. Moreover, IL-13 stimulation can block ciliated cell differentiation from human basal airway epithelial cells. Coincident with IL-13 cellular remodeling are reported decreases in mucociliary transport and ciliary beat frequency. These IL-13-mediated changes in mucociliary function are accompanied by disorganization of cilia, a decrease in the ratio of mucin 5B (MUC5B) to mucin 5AC, and mucus gel tethering to the epithelial surface by mucin 5AC. These airway epithelial responses to IL-13 are mediated by multiple transcription factors, including signal transducer and activator of transcription-6 (STAT6), SAM pointed domain-containing Ets transcription factor (SPDEF), Forkhead box A2 (FOXA2), and Forkhead box J1 (FOXJ1). In addition, analysis of RNA-sequencing data derived from airway epithelial cells shows how IL-13 stimulation promotes broad changes in gene expression across the transcriptome. These results reveal the plastic nature of airway epithelial cells that enables the epithelium to undergo remodeling and functional shifts in response to IL-13 stimulation. With use of new technology, future studies should lead to greater understanding of how IL-13 and other stimuli of disease bring about airway epithelial remodeling, which may aid in the development of therapies that ameliorate airway dysfunction in asthma and other diseases.

Keywords: airway epithelium; asthma; interleukin-13 (IL-13); mucin 5ac (MUC5AC); type 2 inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Airway Remodeling
  • Animals
  • Asthma / metabolism
  • Cell Differentiation
  • Cytokines / metabolism
  • Epithelial Cells / metabolism
  • Gene Expression
  • Humans
  • Interleukin-13 / metabolism*
  • Mice
  • Mucin 5AC / metabolism*
  • Proto-Oncogene Proteins c-ets / genetics*
  • Respiratory Mucosa / metabolism*
  • STAT6 Transcription Factor / genetics*
  • Signal Transduction

Substances

  • Cytokines
  • Interleukin-13
  • MUC5AC protein, human
  • Mucin 5AC
  • Proto-Oncogene Proteins c-ets
  • SPDEF protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • interleukin-13, human