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 October 1, 2018; First published February 1, 2011
Citation Information: J Clin Invest. 2011;121(3):941-955. https://doi.org/10.1172/JCI43584.
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Categories: 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 7

Caveolin 1 deficiency results in enhanced signaling responses of sAgs to levels similar to that induced by pAgs in WT BMMCs.

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Caveolin 1 deficiency results in enhanced signaling responses of sAgs to...
(A) Association of IgE/FcεRI complexes (red) with lipid rafts (green) in sensitized Cav+/+ and Cav–/– BMMCs at different times after exposure to sAgs. Arrows denote examples of colocalization of IgE/FcεRI complexes with lipid rafts. Arrowheads denote areas in which IgE/FcεRI complexes have separated from lipid rafts. Scale bars: 5 μm. Data are representative of 3 separate experiments. (B) FcεRI-γ chain and tyrosine-phosphorylated proteins in pooled lipid raft fractions from sensitized Cav+/+ and Cav–/– BMMCs challenged with sAgs or pAgs. Arrows denote bands that were enhanced by sAgs in Cav–/– BMMCs. Arrowhead denotes a band that did not appear to change in strength in Cav–/– BMMCs. (C) Levels of IL-4 produced by sensitized Cav–/– and Cav+/+ BMMCs 1 hour after sAg or pAg exposure (n = 4). BAL eosinophil counts (D), and lung histology (E) evoked by sAgs or pAgs in sensitized Wsh mice reconstituted with Cav–/– BMMCs or Cav+/+ BMMCs (n = 5). (C–E) §P < 0.01 versus vehicle controls; *P < 0.01 versus Cav+/+ sAg; #P < 0.01 versus Cav+/+ sAg. (F) Histology of lungs from sensitized Wsh mice reconstituted with Cav–/– BMMCs or Cav+/+ BMMCs after exposure to sAgs or pAgs. Samples were stained with H&E. Eosinophil accumulation around small bronchioles and vasculature is denoted. Each histological photomicrograph is representative of 4 mice. Scale bars: 25 μm.