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Eosinophil trafficking: new answers to old questions

Selective tissue accumulation of eosinophils is one of the hallmarks of allergic disease. The mechanisms controlling eosinophil trafficking involve a combination of IL-5dependent eosinophilopoiesis, regulation of adhesion and chemoattractant-dependent interactions with vascular endothelium and control of the fate of the eosinophil in tissue by the integration of adhesion and chemotactic signals delivered by matrix proteins and structural cells. Two papers in this issue of the journal add further information. One study reports anti-thrombin III as a new chemoattractant binding to Syndecan-4 and a second study reveals the release of granulocyte macrophage-colony stimulating factor and regulated on activation, normal T cells expressed and secreted by rhinovirus-infected tracheal submucosal glands. The way in which these new observations fit into the eosinophil trafficking jigsaw will be discussed. A characteristic and histologically striking feature of allergic diseases such as asthma and allergic rhinitis is the up to 100-fold increase in the accumulation of eosinophils at inflammatory sites. This finding is distinctive not least because in the normal state these cells are largely absent from tissues other than the gut where constitutive migration is controlled by eotaxin and a4b7 binding to MAdCAM-1 [1]. A tissue eosinophilia is often a relatively selective event without any increase in other leucocyte subsets such as T cells and neutrophils. Indeed together with lymphocyte homing eosinophil accumulation is one of the best-studied models of the molecular mechanisms involved in selective leucocyte migration, reviewed in [2–4] (Fig. 1). Selective pressure on eosinophil accumulation occurs at every stage in the life cycle of the eosinophil. IL-5 is crucially important as a selective growth factor and together with eosinophil-specific chemoattractants such as eotaxin can cause egress of eosinophils from the bone marrow compartment without affecting other leucocytes [5]. The post-capillary venular endothelium is a major control point for leucocyte migration involving a series of obligate steps each controlled by distinct families of adhesion receptors and chemoattractants, which allows for considerable combinatorial diversity [6]. The capture step involving selectins and a4 integrins appears to be of particular importance in controlling eosinophil migration. The modest but specific increase in endothelial P-selectin and VCAM-1 expression on endothelial cells induced by IL-4 and IL-13 are sufficient to mediate adhesion of eosinophils but not neutrophils under physiological flow conditions through binding to P-selectin glycoprotein 1 (PSGL-1) and VLA-4 (a4b7) [7, 8]. This is because higher levels of PSGL-1 expression on eosinophils result in greater avidity for P-selectin than neutrophils, particularly at the low levels of P-selectin expression induced by the Th2 cytokines and because human neutrophils do not express VLA-4 [9–11]. Eosinophils bind relatively poorly to E-selectin, expression of which is induced by Th1-associated cytokines such as IFN-g and TNF-a and unaffected by IL-4 or IL-13 [12]. The contribution of the activation step in selective eosinophil adhesion to endothelium remains uncertain. The paradigm of leucocyte trafficking anticipates that eosinophils should arrest as a result of exposure to endothelial chemoattractants. These include chemokines binding to eosinophil chemokine receptors, in particular CCR3. Although eosinophils will readily go from a rolling to an arrested phenotype on cytokine-activated endothelium under flow conditions when stimulated exogenously with chemoattractants the evidence for an endogenous chemoattractant is less clear cut. In particular pertussis toxin (PT), which inhibits most chemoattractant-mediated activation events, and an anti-CCR3 mAb only partially inhibited eosinophil arrest on endothelium under flow conditions [13]. In our hands eosinophils continue to roll on cytokine-activated endothelium under flow conditions unless exogenously stimulated (personal observation) although not all investigators have found this [8, 14]. In a recent study eotaxin 3, one of the several ligands for CCR3, was involved in eosinophil transmigration through IL-4-stimulated endothelium [15]. Interestingly however in the CCR3 gene-deleted mouse the eosinophils appeared to be able to migrate through the endothelial cells, but not the endothelial basement membrane suggesting that in the mouse model of asthma CCR3 binding chemokines are important in migration into tissue but not in adhesion and transmigration through endothelium [16]. Lymphocyte function antigen-1 and Mac-1 binding to intercellular adhesion molecule (ICAM)-1 and ICAM-2 play essential roles in the arrest of eosinophils on endothelium and in transmigration. However, this pathway is shared by all other leucocyte subsets [17]. VLA-4/VCAM-1 is also involved in eosinophil arrest on TNF-a-stimulated endothelium [14], but there appears to be no major bias in the binding of subsets of leucocytes to TNF-a-stimulated endothelium [18]. Transmigration of leucocytes requires active involvement of the endothelium with remodelling of tight junctions to allow egress of the cell. The leucocyte also has to penetrate the endothelial basement membrane, probably by activation of metalloproteinases such as MMP-9 [19]. There is no evidence for eosinophil selective components to these events, but they have not been intensively studied. In the lung, migration into the bronchial mucosa is through the systemic bronchial circulation. However, migration into the alveolar compartment that is relevant to interstitial lung diseases such as eosinophilic pneumonia is through the low pressure pulmonary vasculature where the capture step is less important, particularly in the capillary bed and is more likely to be dependent on chemoattractants alone. Consistent with this selectins are not Clin Exp Allergy 2004; 34:676–679 doi:10.1111/j.1365-2222.2004.01944.x