Endotoxin Exposure during Sensitization to Blomia tropicalis Allergens Shifts TH2 Immunity Towards a TH17-Mediated Airway Neutrophilic Inflammation: Role of TLR4 and TLR2

PLoS One. 2013 Jun 21;8(6):e67115. doi: 10.1371/journal.pone.0067115. Print 2013.

Abstract

Experimental evidence and epidemiological studies indicate that exposure to endotoxin lipopolysaccharide (eLPS) or other TLR agonists prevent asthma. We have previously shown in the OVA-model of asthma that eLPS administration during alum-based allergen sensitization blocked the development of lung TH2 immune responses via MyD88 pathway and IL-12/IFN-γ axis. In the present work we determined the effect of eLPS exposure during sensitization to a natural airborne allergen extract derived from the house dust mite Blomia tropicalis (Bt). Mice were subcutaneously sensitized with Bt allergens co-adsorbed onto alum with or without eLPS and challenged twice intranasally with Bt. Cellular and molecular parameters of allergic lung inflammation were evaluated 24 h after the last Bt challenge. Exposure to eLPS but not to ultrapure LPS (upLPS) preparation during sensitization to Bt allergens decreased the influx of eosinophils and increased the influx of neutrophils to the airways. Inhibition of airway eosinophilia was not observed in IFN-γdeficient mice while airway neutrophilia was not observed in IL-17RA-deficient mice as well in mice lacking MyD88, CD14, TLR4 and, surprisingly, TLR2 molecules. Notably, exposure to a synthetic TLR2 agonist (PamCSK4) also induced airway neutrophilia that was dependent on TLR2 and TLR4 molecules. In the OVA model, exposure to eLPS or PamCSK4 suppressed OVA-induced airway inflammation. Our results suggest that B. tropicalis allergens engage TLR4 that potentiates TLR2 signaling. This dual TLR activation during sensitization results in airway neutrophilic inflammation associated with increased frequency of lung TH17 cells. Our work highlight the complex interplay between bacterial products, house dust mite allergens and TLR signaling in the induction of different phenotypes of airway inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology
  • Allergens / toxicity*
  • Animals
  • Asthma / chemically induced
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / pathology
  • Disease Models, Animal
  • Eosinophils / immunology
  • Eosinophils / pathology
  • Lipopolysaccharides / toxicity*
  • Mice
  • Mice, Knockout
  • Neutrophils / immunology*
  • Neutrophils / pathology
  • Pulmonary Eosinophilia / chemically induced
  • Pulmonary Eosinophilia / genetics
  • Pulmonary Eosinophilia / immunology
  • Pulmonary Eosinophilia / pathology
  • Pyroglyphidae / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Th2 Cells / immunology*
  • Th2 Cells / pathology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*

Substances

  • Allergens
  • Lipopolysaccharides
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4

Grants and funding

This study was supported by grants 07/03031-3 and 11/17880-8 from the State of Sao Paulo Foundation for Research Support (FAPESP), CAPES, Brazilian Council of Scientific and Technologic Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.