Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-Releasing Peptide

Am J Respir Cell Mol Biol. 2018 Mar;58(3):341-351. doi: 10.1165/rcmb.2017-0071OC.


Ozone and obesity both increase IL-17A in the lungs. In mice, obesity augments the airway hyperresponsiveness and neutrophil recruitment induced by acute ozone exposure. Therefore, we examined the role of IL-17A in obesity-related increases in the response to ozone observed in obese mice. Lean wild-type and obese db/db mice were pretreated with IL-17A-blocking or isotype antibodies, exposed to air or ozone (2 ppm for 3 h), and evaluated 24 hours later. Microarray analysis of lung tissue gene expression was used to examine the mechanistic basis for effects of anti-IL-17A. Compared with lean mice, ozone-exposed obese mice had greater concentrations of BAL IL-17A and greater numbers of pulmonary IL-17A+ cells. Ozone-induced increases in BAL IL-23 and CCL20, cytokines important for IL-17A+ cell recruitment and activation, were also greater in obese mice. Anti-IL-17A treatment reduced ozone-induced airway hyperresponsiveness toward levels observed in lean mice. Anti-IL-17A treatment also reduced BAL neutrophils in both lean and obese mice, possibly because of reductions in CXCL1. Microarray analysis identified gastrin-releasing peptide (GRP) receptor (Grpr) among those genes that were both elevated in the lungs of obese mice after ozone exposure and reduced after anti-IL-17A treatment. Furthermore, ozone exposure increased BAL GRP to a greater extent in obese than in lean mice, and GRP-neutralizing antibody treatment reduced obesity-related increases in ozone-induced airway hyperresponsiveness and neutrophil recruitment. Our data indicate that IL-17A contributes to augmented responses to ozone in db/db mice. Furthermore, IL-17A appears to act at least in part by inducing expression of Grpr.

Keywords: CXCL1; airway hyperresponsiveness; gastrin-releasing peptide receptor; microarray; neutrophil.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Blocking / pharmacology
  • Chemokine CCL20 / immunology
  • Chemokine CXCL1 / immunology
  • Female
  • Gastrin-Releasing Peptide / immunology*
  • Interleukin-17 / immunology*
  • Interleukin-23 Subunit p19 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration / immunology
  • Neutrophils / immunology
  • Obesity / pathology*
  • Ozone / toxicity*
  • Receptors, Bombesin / genetics
  • Receptors, Bombesin / metabolism*
  • Respiratory Hypersensitivity / immunology*


  • Antibodies, Blocking
  • CCL20 protein, mouse
  • Chemokine CCL20
  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Il17a protein, mouse
  • Il23a protein, mouse
  • Interleukin-17
  • Interleukin-23 Subunit p19
  • Receptors, Bombesin
  • Ozone
  • Gastrin-Releasing Peptide