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Defective eosinophil hematopoiesis ex vivo in inbred Rocky Mountain White (IRW) mice.

ABSTRACT: We examine the proliferation and differentiation of bone marrow (BM) progenitors from inbred Rocky Mountain White (IRW) mice, a strain used primarily for retrovirus infection studies. In contrast to findings with BALB/c and C57BL/6 strains, IRW BM cells cannot proliferate or generate pure eosinophil cultures ex vivo in response to a defined cytokine regimen. Analysis of IRW BM at baseline was unremarkable, including 0.08 ± 0.03% Lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic stem cells and 5.2 ± 0.3% eosinophils; the percentage of eosinophil progenitors (EoPs; Lin(-)Sca-1(-)c-kit(+)CD34(+)IL-5R?(+)) was similar in all three mouse strains. Transcripts encoding GM-CSFR? and the IL-3/IL-5/GM-CSF common ? chain were detected at equivalent levels in IRW and BALB/c BM, whereas expression of transcripts encoding IL-5R?, IL-3R?, and GATA-2 was diminished in IRW BM compared with BALB/c. Expression of membrane-bound IL-5R? and intracellular STAT5 proteins was also diminished in IRW BM cells. Diminished expression of transcripts encoding IL-5R? and GATA-2 and immunoreactive STAT5 in IRW BM persisted after 4 days in culture, along with diminished expression of GATA-1. Western blot revealed that cells from IRW BM overexpress nonsignaling soluble IL-5R? protein. Interestingly, OVA sensitization and challenge resulted in BM and airway eosinophilia in IRW mice; however, the responses were significantly blunted. These results suggest that IRW mice have diminished capacity to generate eosinophils in culture and in vivo, likely as a result of diminished signaling via IL-5R?.

SUBMITTER: Dyer KD

PROVIDER: S-EPMC3236555 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Defective eosinophil hematopoiesis ex vivo in inbred Rocky Mountain White (IRW) mice.

Dyer Kimberly D KD Garcia-Crespo Katia E KE Percopo Caroline M CM Bowen Aaron B AB Ito Tomonobu T Peterson Karin E KE Gilfillan Alasdair M AM Rosenberg Helene F HF

Journal of leukocyte biology 20110830 6

We examine the proliferation and differentiation of bone marrow (BM) progenitors from inbred Rocky Mountain White (IRW) mice, a strain used primarily for retrovirus infection studies. In contrast to findings with BALB/c and C57BL/6 strains, IRW BM cells cannot proliferate or generate pure eosinophil cultures ex vivo in response to a defined cytokine regimen. Analysis of IRW BM at baseline was unremarkable, including 0.08 ± 0.03% Lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic stem cells and 5.2 ± 0.3 ...[more]

PMID: 21878543

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Project description:BACKGROUND:Eosinophils are immunomodulatory leucocytes 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 allergen-challenged wild-type mice are capable of prolonged survival ex vivo, in contrast to eosinophils from both untreated and fungal allergen-challenged IL5tg mice, which undergo rapid demise in the absence of exogenous cytokine support. TNF-α (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 TNF-α gene deletion nor anti-TNF-α 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.

Dataset Information

Defective eosinophil hematopoiesis ex vivo in inbred Rocky Mountain White (IRW) mice.

Publications

Defective eosinophil hematopoiesis ex vivo in inbred Rocky Mountain White (IRW) mice.

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