Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation
Cong Jin, … , W. Michael Foster, Soman N. Abraham
Cong Jin, … , W. Michael Foster, Soman N. Abraham
Published February 1, 2011
Citation Information: J Clin Invest. 2011;121(3):941-955. https://doi.org/10.1172/JCI43584.
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Research Article Cell biology Immunology Inflammation Pulmonology

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

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 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.

Authors

Cong Jin, Christopher P. Shelburne, Guojie Li, Kristina J. Riebe, Gregory D. Sempowski, W. Michael Foster, Soman N. Abraham

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Figure 6

The endocytic and signaling responses of BMMCs to sAgs following pretreatment with latrunculin B (Lat B) is comparable to responses evoked by pAgs in untreated BMMCs.

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The endocytic and signaling responses of BMMCs to sAgs following pretrea...
(A) Association of IgE/FcεRI complexes (red) with lipid raft domains (green) in latrunculin B–treated and untreated BMMCs after exposure to sAgs. Arrows denote examples of colocalization of IgE/FcεRI complexes with lipid rafts. Arrowheads denote areas where IgE/FcεRI complexes have separated from lipid rafts. (B) Dynamic localization of sAgs (red) within GFP-CD63+ (green) compartments in latrunculin B–treated and untreated BMMCs. (A and B) Original magnification, ×100. Scale bars: 5 μm. (C) Western blot to detect FcεRI-γ chain and tyrosine-phosphorylated proteins in pooled lipid raft fractions. Arrows denote bands that were enhanced by sAgs following latrunculin B treatment. Arrowhead denotes a band that did not appear to change in strength after latrunculin B treatment. Data in A–C are representative of 3 separate experiments. (D) Latrunculin B–treated BMMCs expressed higher levels of IL-4 than did untreated BMMCs 1 hour after sAg exposure (n = 4). *P < 0.01 versus untreated BMMCs; §P < 0.01 versus vehicle. The enhanced level of IL-4 expression was comparable to that induced by pAgs in untreated BMMCs (black bar).