Eosinophilopoiesis in A Murine Model of Allergic Airway Eosinophilia: Involvement of Bone Marrow IL-5 and IL-5 Receptor α

Abstract

The airway inflammation in asthma is dominated by eosinophils. The aim of this study was to elucidate the contribution of newly produced eosinophils in airway allergic inflammation and to determine mechanisms of any enhanced eosinophilopoiesis. OVA-sensitized BALB/c mice were repeatedly exposed to allergen via airway route. Newly produced cells were identified using a thymidine analog, 5-bromo-2′-deoxyuridine, which is incorporated into DNA during mitosis. Identification of IL-5-producing cells in the bone marrow was performed using FACS. Bone marrow CD3+ cells were enriched to evaluate IL-5-protein release in vitro. Anti-IL-5-treatment (TRFK-5) was given either systemically or directly to the airways. IL-5R-bearing cells were localized by immunocytochemistry. Repeated airway allergen exposure caused prominent airway eosinophilia after three to five exposures, and increased the number of immature eosinophils in the bone marrow. Up to 78% of bronchoalveolar lavage (BAL) granulocytes were 5-bromo-2′-deoxyuridine positive. After three allergen exposures, both CD3+ and non-CD3 cells acquired from the bone marrow expressed and released IL-5-protein. Anti-IL-5 given i.p. inhibited both bone marrow and airway eosinophilia. Intranasal administration of anti-IL-5 also reduced BAL eosinophilia, partly via local effects in the airways. Bone marrow cells, but not BAL eosinophils, displayed stainable amounts of the IL-5R α-chain. We conclude that the bone marrow is activated by airway allergen exposure, and that newly produced eosinophils contribute to a substantial degree to the airway eosinophilia induced by allergen. Airway allergen exposure increases the number of cells expressing IL-5-protein in the bone marrow. The bone marrow, as well as the lung, are possible targets for anti-IL-5-treatment.

Dendritic cells from Chlamydia‐infected mice show altered Toll‐like receptor expression and play a crucial role in inhibition of allergic responses to ovalbumin

“…Previous studies in human and mouse systems have shown that local allergen exposure results in enhanced eosinophilopoiesis in BM. This prominently contributes to local eosinophilia, possibly via a feedback mechanism existing between the local tissue and BM, which triggers allergic inflammatory reaction [32][33][34]. Recent studies have shown that eosinophil precursors in BM are identifiable as CD34 + /IL-5R § + cells [35].…”

Allergen exposure–induced differences in CD34+ cell phenotype: relationship to eosinophilopoietic responses in different compartments

“…This finding is in agreement with our previous report, in which no significant allergen-induced changes in total number of BrdU ϩ cells in BM were observed. 7 However, allergen exposure induced a significant increase in CD34 ϩ cells in blood and BALf, where newly produced CD34 ϩ cells substantially contributed to the observed increase. After allergen exposure, newly produced CD34 ϩ cells comprised around 75% of total BALf CD34 ϩ cells and about 85% of total blood CD34 ϩ cells.…”

“…1,2 Accumulation of inflammatory cells is considered to be the result of increased production and traffic of cells from bone marrow (BM) into AW via the circulation. [3][4][5][6][7][8] Eosinophils develop from CD34 ϩ hematopoietic progenitor cells. CD34 is a stage-specific rather than a lineage-specific leukocyte-differentiation antigen.…”

“…Also, we assumed that the phenotype of AW eosinophils depends on whether these cells were differentiated within the BM or AW compartment. To assess our hypothesis, we used a mouse model of eosinophilic inflammation induced by ovalbumin (OVA), 7,15 in which newly produced cells were labeled with 5Ј-bromo-2Ј-deoxyuridine (BrdU). Also, we used in vitro cell-culture techniques to assess eosinophil colony-forming activity and IL-5 release from AW CD34 ϩ cells.…”

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

“…[42][43][44] The administration of sIL-4R or antagonistic IL-4 mutant proteins is a novel approach to inhibit allergic inflammation. These proteins directly inhibit IL-4 binding and do not induce host immune responses to these proteins.…”