T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia

J Immunol. 2013 Sep 15;191(6):3100-11. doi: 10.4049/jimmunol.1301360. Epub 2013 Aug 21.

Abstract

Th17 cells are a proinflammatory subset of effector T cells that have been implicated in the pathogenesis of asthma. Their production of the cytokine IL-17 is known to induce local recruitment of neutrophils, but the direct impact of IL-17 on the lung epithelium is poorly understood. In this study, we describe a novel mouse model of spontaneous IL-17-driven lung inflammation that exhibits many similarities to asthma in humans. We have found that STAT3 hyperactivity in T lymphocytes causes an expansion of Th17 cells, which home preferentially to the lungs. IL-17 secretion then leads to neutrophil infiltration and lung epithelial changes, in turn leading to a chronic inflammatory state with increased mucus production and decreased lung function. We used this model to investigate the effects of IL-17 activity on airway epithelium and identified CXCL5 and MIP-2 as important factors in neutrophil recruitment. The neutralization of IL-17 greatly reduces pulmonary neutrophilia, underscoring a key role for IL-17 in promoting chronic airway inflammation. These findings emphasize the role of IL-17 in mediating neutrophil-driven pulmonary inflammation and highlight a new mouse model that may be used for the development of novel therapies targeting Th17 cells in asthma and other chronic pulmonary diseases.

Publication types

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

MeSH terms

  • Animals
  • Asthma / immunology*
  • Asthma / metabolism
  • Cell Separation
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Immune System Diseases / immunology*
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Leukocyte Disorders / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / immunology*
  • Pneumonia / immunology
  • Pneumonia / metabolism
  • Real-Time Polymerase Chain Reaction
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Transfection

Substances

  • Interleukin-17

Supplementary concepts

  • Neutrophil Chemotactic Response, Abnormal