Eosinophil development, regulation of eosinophil-specific genes, and role of eosinophils in the pathogenesis of asthma

Abstract

Eosinophils arise from hematopoietic CD34(+) stem cells in the bone marrow. They acquire IL-5Rα on their surface at a very early stage during eosinophilopoiesis, and differentiate under the strong influence of interleukin (IL)-5. They then exit to the bloodstream, and enter the lung upon exposure to airway inflammatory signals, including eotaxins. In inflamed tissues, eosinophils act as key mediators of terminal effector functions and innate immunity and in linking to adaptive immune responses. Transcription factors GATA-1, CCAAT/enhancer-binding protein, and PU.1 play instructive roles in eosinophil specification from multipotent stem cells through a network of cooperative and antagonistic interactions. Not surprisingly, the interplay of these transcription factors is instrumental in forming the regulatory circuit of expression of eosinophil-specific genes, encoding eosinophil major basic protein and neurotoxin, CC chemokine receptor 3 eotaxin receptor, and IL-5 receptor alpha. Interestingly, a common feature is that the critical cis-acting elements for these transcription factors are clustered in exon 1 and intron 1 of these genes rather than their promoters. Elucidation of the mechanism of eosinophil development and activation may lead to selective elimination of eosinophils in animals and human subjects. Furthermore, availability of a range of genetically modified mice lacking or overproducing eosinophil-specific genes will facilitate evaluation of the roles of eosinophils in the pathogenesis of asthma. This review summarizes eosinophil biology, focusing on development and regulation of eosinophil-specific genes, with a heavy emphasis on the causative link between eosinophils and pathological development of asthma using genetically modified mice as models of asthma.

Keywords: Asthma; CCR3; GATA-1; IL-5; eosinophils; eotaxin.

Fig. 1

Eosinophils. (A) Peripheral blood eosinophils purified by negative selection. (B) and (C) Cord blood-derived eosinophils. Cord blood CD34⁺ cells were cultured for 18 days with a cytokine cocktail. Cultured cells were stained with Diff Quick (B) or probed with FITC-conjugated anti-MBP antibody (C). DAPI and MBP stains are shown in blue and green, respectively.

Fig. 2

Eosinophil development. (A) Transcription factors regulating eosinophil commitment and maturation. Eosinophil commitment is dictated largely by two transcription factors, CCAAT/enhancer-binding protein (C/EBP) and GATA-1, whose levels and functions are fine-tuned by interactions with the other transcription factors PU.1 and friend of GATA (FOG). Icsbp and Id1 individually regulate eosinophil formation, although their relationship with C/EBP and GATA-1 are unknown. Eosinophil maturation is driven by a similar combination of transcription factors but is inhibited by C/EBPe. Notch signaling prevents eosinophil maturation by an unknown mechanism. (B) Different pathways of eosinophil development in the mouse and human. Human eosinophil progenitors arise directly from a common myeloid progenitor, whereas mouse eosinophil progenitors arise from a common myeloid progenitor via a granulocyte/macrophage progenitor that is bipotent for eosinophils and neutrophils.

Fig. 3

Regulatory regions of eosinophil-specific genes. Transcription factor binding sites in the MBP (NM002728.4), EDN (NM002934.2), ECP (NM002935.2), EPO (NM000502.4), CCR3 (NM001837.3), and IL-5α genes (NM000564.3). Functional binding sites are indicated by dark figures, and putative binding sites that have not been confirmed as functional are indicated by light figures. Numbering is relative to the transcriptional start site of each gene.