Eosinophils are in the swim!

The freshwater tropical fish, Danio rerio, has most certainly arrived. A species previously familiar only to aquarium enthusiasts, the zebrafish has moved into a central role as a unique and flexible model for the study of vertebrate biology, in fields including embryology and neurobiology, and, more recently extending to hematopoiesis, immunology, and infectious disease.^1,2 

In this issue of Blood, Balla et al³  present a detailed examination of zebrafish eosinophils, an enigmatic leukocyte lineage whose role in promoting homeostasis and host defense remains uncertain despite years of research with more traditional human, mouse, and guinea pig model systems.^4,5  Among the highlights of this article is an exquisite atlas of zebrafish eosinophil morphology; the authors document the isolation of gata2-expressing cells from whole-kidney marrow, coloration with standard cytology stains, and prevalence of eosinophilic myelocytes, metamyelocytes, bands, and polymorphonuclear forms with both light and electron microscopic images. In an interesting contrast to mammalian biology, the zebrafish polymorphonuclear eosinophils are found only rarely, making their discovery worthy of further consideration.

Will zebrafish stand ahead of mice as the new organism of choice for studies of eosinophil-mediated function in health and disease? Balla and colleagues³  clearly demonstrate that zebrafish eosinophils are not only readily recognizable, but also maintain important functional features. For instance, zebrafish eosinophils, similar to their human counterparts, degranulate in the response to appropriate challenge. However, several findings in the article introduce some question as to exactly what might be found in the zebrafish eosinophil granules. The authors report eosinophil-specific transcription of dr-RNase-2⁶ —an ortholog of the divergent human and mouse eosinophil ribonucleases, and 1 of the 3 RNase A ribonucleases encoded in the zebrafish genome. Yet ortholog(s) of eosinophil major basic protein (MBP), a highly conserved secretory granule protein to which many of the current functions of eosinophils are attributed, have not been detected. As such, what exactly is inside the zebrafish eosinophil granule? Are proinflammatory cytokines more prominent in zebrafish than they are in the mammalian eosinophil granules? Lee and Lee⁷  have argued that release of cationic granule proteins is not as crucial physiologically as it has been perceived to be historically; perhaps the zebrafish model will permit us to evaluate this hypothesis directly (see figure).

The authors also demonstrate peripheral eosinophilia in response to allergen challenge and similarly, accumulation of eosinophils in tissues in response to parasitic infection. Nonetheless, it is not at all clear what promotes this response at the biochemical level. In mammalian biology, eosinophilia in response to these stimuli is directly dependent on the actions of the Th2 cytokine, interleukin-5 (IL-5), which promotes eosinophil colony expansion, eosinophil priming, and prolonged eosinophil survival in the periphery.⁹  Similar to what was described above for MBP, analysis of the zebrafish genome has not revealed any sequences orthologous to mammalian IL-5, nor any that are related to its unique receptor, although other Th2 cytokine and cytokine receptor sequences have been identified, as have zebrafish orthologs of eotaxin (CCL11), a chemokine with unique eosinophil chemoattractant properties.

In summary, Balla and colleagues³  have provided us with an important new perspective on eosinophil hematopoiesis and a fresh start from which to examine the role of eosinophils in eliciting disease and promoting homeostasis. If the sea hath fish for every man, those of us working in eosinophil biology are certainly happy to know about Danio rerio.