Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation

J Clin Invest. 2011 Mar;121(3):941-55. doi: 10.1172/JCI43584.

Abstract

Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft–enriched, CD63(+) endocytic compartments, which prolonged IgE/FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.

Publication types

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

MeSH terms

  • Air Pollutants
  • Allergens / chemistry*
  • Animals
  • Antigens, CD / biosynthesis
  • Asthma / metabolism*
  • Bronchial Hyperreactivity / immunology*
  • Disease Models, Animal
  • Endocytosis
  • Gene Expression Regulation*
  • Hypersensitivity / metabolism*
  • Immunoglobulin E / metabolism*
  • Inflammation
  • Lipids / chemistry
  • Male
  • Mast Cells / cytology*
  • Membrane Microdomains
  • Mice
  • Mice, Inbred C57BL
  • Platelet Membrane Glycoproteins / biosynthesis
  • Tetraspanin 30

Substances

  • Air Pollutants
  • Allergens
  • Antigens, CD
  • Cd63 protein, mouse
  • Lipids
  • Platelet Membrane Glycoproteins
  • Tetraspanin 30
  • Immunoglobulin E