Eosinophil persistence in vivo and sustained viability ex vivo in response to respiratory challenge with fungal allergens

Abstract

Background

Eosinophils are immunomodulatory leukocytes that contribute to the pathogenesis of Th2 driven asthma and allergic lung diseases.

Objective

Our goal was to identify unique properties of eosinophils recruited to the lungs and airways of mice in response to challenge with asthma-associated fungal allergens.

Methods

Mice were challenged intranasally on days 0, 3 and 6 with a filtrate of Alternaria alternata. Recruited eosinophils were enumerated in bronchoalveolar lavage fluid. Eosinophils were also isolated from lungs of mice sensitized and challenged with Aspergillus fumigatus and evaluated ex vivo in tissue culture.

Results

Eosinophils persist in the airways for several weeks in response to brief provocation with A. alternata in wild-type, Gm-csf- and eotaxin-1-gene-deleted mice, while eosinophils are recruited but do not persist in the absence of IL-13. Eosinophils isolated from the lungs A. alternata-challenged mice are cytokine-enriched compared to those from IL5tg mice, including 800-fold higher levels of eotaxin-1. Furthermore, eosinophils from the lungs and spleen of fungal-challenged wild-type are capable of prolonged survival ex vivo, in contrast to eosinophils from both un-treated and fungal-allergen challenged IL5tg mice, which undergo rapid demise in the absence of exogenous cytokine support. TNFα (but not IL5, IL-3, eotaxin-1 or GM-CSF) was detected in supernatants of ex vivo eosinophil cultures from the lungs of fungal-allergen challenged wild-type mice. However, neither TNFα gene-deletion nor anti-TNFα neutralizing antibodies had any impact sustained eosinophil survival ex vivo.

Conclusion and Clinical Relevance

Eosinophils are phenotypically and functionally heterogeneous. As shown here, eosinophils from fungal-allergen challenged wild-type mice maintain a distinct cytokine profile, and, unlike eosinophils isolated from IL5tg mice, they survive ex vivo in the absence of exogenous pro-survival cytokine support. As treatments for asthma currently in development focus on limiting eosinophil viability via strategic cytokine blockade, the molecular mechanisms underlying differential survival merit further investigation.

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