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Eosinophil apoptosis in allergic diseases — an emerging new issue

It is clear that an important issue such as cell homeostasis must be controlled in a multicellular organism. However, as any other mechanism, the control of cell numbers can also be dysregulated under pathological conditions. For instance, inflammatory diseases are normally associated with an increase in the numbers of inflammatory cells. Therefore, allergologists have occupied themselves with trying to understand the marked accumulation of eosinophils associated with chronic allergic inflammation for many years. In this issue of Clinical and Experimental Allergy , Kodamaet al. [1] report on the role of eosinophil apoptosis in vivo in a mouse model of eosinophilic inflammation. In this study, apoptotic eosinophils were identified using electron microscopy and a specific technique to identify DNA fragmentation, a hallmark of apoptotic cells. The data by Kodamaet al. suggest that the resolution of eosinophilic inflammation is most likely the consequence of the induction of eosinophil apoptosis. These findings are not surprising since apoptosis is the most common form of physiological cell death. Moreover, the resolution of eosinophilic inflammation and its association with eosinophil apoptosis has been previously described in in vivomouse [2] and human [3] systems. Taken together, the importance of apoptosis for the removal of eosinophils in vivo is now well established. Perhaps more exciting is the fact that apoptosis can be dysregulated and may then contribute to pathogenic processes. For instance, defective regulation of apoptosis may play a part in the aetiology of cancer, AIDS, autoimmune diseases, and neurodegenerative disorders [4,5]. Interestingly, the process of eosinophil apoptosis is delayed in allergic inflammatory sites [6] and, perhaps, also in the blood [7] of atopic patients. Therefore, it appears that delayed apoptosis contributes to the accumulation of these cells in chronic allergic inflammation. The article by Kodama et al. [1] also provides evidence for a delayed apoptotic eosinophil death, although a direct demonstration has yet to be provided in their model of eosinophilic inflammation. In addition, the suggested delay of eosinophil death in the current study [1] does not appear to be as dramatic as observed in nasal polyp tissues [6]. The reason for this could be that the ovalbumin-sensitized and challenged mouse represents an acute inflammatory response and may not be the best model for studying chronic eosinophilic inflammation. Why is the mechanism of delayed eosinophil apoptosis important for the specific accumulation of this cell type in chronic allergic responses? Previously published work suggests that eosinophils specifically adhere to the endothelium and migrate into tissues with the help of eosinophil-specific chemoattractants. For instance, IL-4, an important cytokine in allergic responses, induces vascular cell adhesion molecule (VCAM)-1 in microvascular endothelial cells. VCAM1 binds to cells bearing the integrin very late antigen (VLA)4. The expression of VLA-4 by eosinophils, but not neutrophils, suggests that the VCAM-1/VLA-4 adhesion pathway contributes to the preferential migration of eosinophils into allergic inflammatory sites [8,9]. However, eosinophilia have also been observed under conditions where IL-4 is not or barely expressed [6,10]. On the other hand, mice over-expressing IL-4 in the lung demonstrated a cellular infiltrate consisting of macrophages, lymphocytes, eosinophils, and neutrophils [11]. Moreover, the intercellular adhesion molecule (ICAM)-1/integrin CD11/ CD18 pathway appears to be equally important for eosinophils and neutrophils [12,13], suggesting that IL-4-induced VCAM-1 expression alone cannot explain the accumulation of eosinophils in allergic inflammation. Another possibility to achieve selectivity in the migration of circulating leucocytes into tissues is the differential expression of receptors for chemoattractants. For instance, eotaxin has been reported to selectively stimulate eosinophils [14,15], although recent reports suggest that eotaxin can also activate basophils [16] and possibly even T cells [17]. Eotaxin binds, like regulated upon activation normal T cells expressed and secreted (RANTES) and monocyte chemotactic protein (MCP)-4, to the chemokine receptor CCR3, which is expressed by eosinophils but not neutrophils, suggesting a possible specific recruitment pathway for eosinophils mediated by these chemokines. However, other chemoattractants present in allergic tissues, such as plateletactivating factor (PAF) [18], complement factors [19], leukotrienes [20], and IL-8 [21], act on both eosinophils and neutrophils. Therefore, it is unlikely that selective accumulation of eosinophils occurs exclusively at the level of chemotaxis. This view is strongly supported by observations i vivo. After antigen challenge, an increased initial, non-specifc recruitment of inflammatory cells, including neutrophils, has been reported in murine and human models [22,23]. Thus, the story of how eosinophils accumulate in tissues appears to be more complicated than we have thought so far. Meanwhile, specific delayed eosinophil apoptosis was