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Originally published online as doi:10.1189/jlb.0607344 on October 10, 2007

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(Journal of Leukocyte Biology. 2008;83:1-12.)
© 2008 by Society for Leukocyte Biology

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Steven R. Barthel*,{dagger}, Mats W. Johansson{dagger}, Dawn M. McNamee*,{dagger} and Deane F. Mosher*,{dagger},1

* Departments of Biomolecular Chemistry and
{dagger} Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA

1 Correspondence: Departments of Biomolecular Chemistry and Medicine, University of Wisconsin-Madison, 4285A Medical Sciences Center, 1300 University Avenue, Madison, WI 53706-1532, USA. E-mail: dfmosher{at}facstaff.wisc.edu


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ABSTRACT
 
Eosinophilic inflammation is a characteristic feature of asthma. Integrins are highly versatile cellular receptors that regulate extravasation of eosinophils from the postcapillary segment of the bronchial circulation to the airway wall and airspace. Such movement into the asthmatic lung is described as a sequential, multistep paradigm, whereby integrins on circulating eosinophils become activated, eosinophils tether in flow and roll on bronchial endothelial cells, integrins on rolling eosinophils become further activated as a result of exposure to cytokines, eosinophils arrest firmly to adhesive ligands on activated endothelium, and eosinophils transmigrate to the airway in response to chemoattractants. Eosinophils express seven integrin heterodimeric adhesion molecules: {alpha}4β1 (CD49d/29), {alpha}6β1 (CD49f/29), {alpha}Mβ2 (CD11b/18), {alpha}Lβ2 (CD11a/18), {alpha}Xβ2 (CD11c/18), {alpha}Dβ2 (CD11d/18), and {alpha}4β7 (CD49d/β7). The role of these integrins in eosinophil recruitment has been elucidated by major advances in the understanding of integrin structure, integrin function, and modulators of integrins. Such findings have been facilitated by cellular experiments of eosinophils in vitro, studies of allergic asthma in humans and animal models in vivo, and crystal structures of integrins. Here, we elaborate on how integrins cooperate to mediate eosinophil movement to the asthmatic airway. Antagonists that target integrins represent potentially promising therapies in the treatment of asthma.

Key Words: cytokine • extravasation • podosome • recruitment • VCAM-1


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INTRODUCTION
 
The eosinophil is a highly motile, white blood cell containing distinctive cytoplasmic granules [1 , 2 ]. First described in 1879 by Paul Ehrlich [1 , 2 ], eosinophils have been studied extensively as potent defenders against parasitic helminths. The cuticles of helminths are destroyed by granule proteins and superoxide radicals released or generated by eosinophils [3 , 4 ]. The view of eosinophils as benign immune sentinels and effectors has become complicated over the past few decades by recognition of the possible deleterious role of eosinophils in immune hypersensitivity syndromes, including asthma, dermatitis, and rhinitis [2 , 5 6 7 8 9 ].

The prevalence of asthma worldwide is increasing for reasons that are unclear [10 11 12 ]. Recruitment of eosinophils to the airway is believed to exacerbate asthma and contribute to the chronic character of asthma [13 , 14 ]. Thus, the study of how eosinophils traffic from blood to the airway is of considerable importance. Integrins, which are among the most versatile of known cellular receptors [15 , 16 ], have generated particular interest as likely determinants of how eosinophils arrest in the postcapillary venules of the bronchi and mediate extravasation of eosinophils from blood to the airway wall and airspace [17 ]. Specifically, integrins have been studied in relationship to rolling and arrest of eosinophils on endothelium, migration through endothelium and the underlying basement membrane, and traversing of bronchial epithelium into the airway lumen [18 , 19 ]. It is important to note that this multistep paradigm of eosinophil and granulocyte diapedesis applies to postcapillary vessels of the bronchial circulation and that movement to the parenchymal tissue of the lung is little understood [20 ].

As depicted in Figure 1 , purified human blood eosinophils express seven integrin heterodimers: {alpha}4β1 (CD49d/29), {alpha}6β1 (CD49f/29), {alpha}Mβ2 (CD11b/18), {alpha}Lβ2 (CD11a/18), {alpha}Xβ2 (CD11c/18), {alpha}Dβ2 (CD11d/18), and {alpha}4β7 (CD49d/β7) [21 22 23 ]. Each type of heterodimer interacts with its own set of ligands, which may be deposited in an extracellular matrix (ECM) or a counter-receptor on other cells. Understanding functions of the integrin complement on a given cell type is complicated by the fact that each integrin may be present in several conformational states, have varying levels of expression, and cluster in the plasma membrane [24 , 25 ]. The movement of eosinophils into the asthmatic lung, therefore, can be expected to involve a complex interplay of integrin receptors in different states of activation, interacting with a diverse set of ligands on bronchial endothelium and cells within tissue.


Figure 1
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  		Figure 1. Integrins of eosinophils. Schematic of the seven heterodimeric integrin adhesion receptors expressed by eosinophils. Functions and ligands assigned to integrins have been deduced in various assays using eosinophils. *, Subunits that contain the insert (I)-domain. Subunits that are underlined contain the I-like domain. MAdCAM-1, Mucosal addressin cell adhesion molecule-1; FG, fibrinogen; LN, laminin; VN, vitronectin.

Although less is known about integrins of the eosinophil in comparison with integrins of lymphocytes, neutrophils, or platelets, considerable information is available about the surface phenotype of the eosinophil, how integrins and integrin effectors dynamically regulate interactions of eosinophils with ligands, and how these interactions lead to properties of eosinophil adhesion, migration, survival, and recruitment in asthma. Here, we summarize recent advances in the comprehension of integrin structure, integrin function, and integrin modulation of eosinophils. Therapeutic implications of such advances are discussed.


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INTEGRINS OF EOSINOPHILS
 
{alpha}4β1 (CD49d/29, VLA-4)
Roles of {alpha}4β1 of eosinophils
{alpha}4β1 has been studied more extensively than other eosinophil integrins because of its role in mediation of rolling at physiological shear rates [26 , 27 ] and adhesion [21 , 28 29 30 31 ] of purified blood or airway eosinophils on VCAM-1 (CD106), which is an integrin counter-receptor up-regulated in the asthmatic lung [32 ]. Figure 2 depicts the arrangement of Ig-like modules of VCAM-1 and the loop in Ig-like module 1 that contains the Ile-Asp-Ser-Pro-Leu (IDSPL) recognition sequence that interacts with {alpha}4β1. Expression of endothelial VCAM-1 is induced by Th2 mediators, strongly implicating VCAM-1 in {alpha}4β1-mediated eosinophil recruitment from blood to the airway of human asthmatics [36 , 37 ]. Endothelial VCAM-1 may also be expressed in response to activators of NF-{kappa}B or of AP-1, including thrombin, homocysteine, angiotensin II, reactive oxygen species, or migration-inhibitory factor [38 39 40 41 42 ]. Eosinophils may even up-regulate local amounts of VCAM-1 on endothelial cells through production of hypothiocyanous acid, a membrane-permeable product that is generated in response to oxidation of thiocyanate by eosinophil peroxidase [43 ]. There is little [44 , 45 ] or no [37 , 46 ] expression of {alpha}4β1 on purified human neutrophils, suggesting that eosinophil recognition of VCAM-1 mediated by {alpha}4β1 is an important mechanism by which selective infiltration of eosinophils over neutrophils is achieved in asthma [47 , 48 ]. Although it has been reported that {alpha}9β1 on neutrophils can mediate migration on VCAM-1 [45 ], in our hands, neutrophils do not adhere to immobilized, recombinant, soluble VCAM-1 (our unpublished results) under conditions in which eosinophils adhere readily [30 , 31 ].


Figure 2
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  		Figure 2. Structure and schematic of VCAM-1 splice forms. Crystal structure of the first two N-terminal Ig-like modules of 6d- and 7d-VCAM-1 [33 ]. The crystal structure is color-coded to match the schematic of VCAM-1 modules depicted to the right. In the crystal structure, module 1 contains an IDSPL loop (highlighted in black) that is recognized by {alpha}4β1 of eosinophils. A second IDSPL motif recognized by {alpha}4β1 of eosinophils is present in module 4 of 7d-VCAM-1, which is also recognized by {alpha}Mβ2. Module 4 is absent from 6d-VCAM-1, the likely result of exon skipping during mRNA splicing [34 ]. Two intra-domain disulfide bonds are present in modules 1 and 4, and modules 2, 3, 6, and 7 are predicted to contain only one such disulfide, which is missing from module 5. Individual modules have been color-coded based on amino acid sequence identity: modules 1 and 4, 73%; modules 2 and 5, 60%; modules 3 and 6, 60%. The internal homology and similarity of intron sizes between modules 1–3 and 4–6 suggest that modules 4–6 may have arisen in evolution by gene duplication of ancestral modules 1–3 [35 ]. The figure was created with RasMol.

In addition to mediating rolling and firm adhesion, {alpha}4β1 supports eosinophil migration on VCAM-1. Thus, blocking antibodies recognizing the {alpha}4 subunit inhibit eosinophil migration through Transwell pores coated with recombinant VCAM-1 in response to RANTES and across VCAM-1-expressing endothelial cells induced by supernatants of PBMCs obtained from antigen-sensitized atopic asthmatics [49 , 50 ]. Migration of eosinophils across endothelial cell monolayers in response to eotaxin is inhibited by anti-{alpha}4 [51 ]. Ligation of {alpha}4β1 by VCAM-1 has been shown to modulate functions beyond eosinophil rolling, adhesion, and migration. That is, adhesion of eosinophils to VCAM-1 potentiates superoxide anion generation [52 53 54 ]. The respiratory burst is inhibited following preincubation with anti-{alpha}4 antibody or the WAY103 small molecule {alpha}4 antagonist [53 ]. In contrast, anti-{alpha}4 or WAY103 enhances eosinophil-derived neurotoxin release from granules of eosinophils adherent to VCAM-1 [53 ]. Thus, ligation of {alpha}4β1 by these two antagonists has different activities—stimulation of granule release and inhibition of respiratory burst.

The β1 subunit localizes to podosomes of blood eosinophils adherent to VCAM-1 [55 ] or of airway eosinophils adherent to VCAM-1, ICAM-1 (CD54), fibrinogen, vitronectin, or albumin [31 ]. The podosome is a transient structure that mediates interaction with and proteolysis of adhesive ligands in ECM [56 ]. Podosomes are enhanced in size and quantity of airway eosinophils adherent to VCAM-1 in comparison with blood eosinophils [31 ], and the increase can be replicated by treatment of blood eosinophils with IL-5 or TNF-{alpha} [55 ]. It is noteworthy that eosinophils do not form the more stable focal adhesions found in fibroblasts adherent to VCAM-1 [55 ]. Airway eosinophils are more migratory than blood eosinophils [57 ]. The increased size and/or number of podosomes of airway eosinophils may, therefore, contribute to the increased mobility.

As described above, the conformational states of integrins determine whether an integrin is functional for cell adhesion and migration. Activation of integrins is accomplished by "inside-out" signaling, whereby chemokines and cytokines interact with cell-surface receptors and initiate signaling pathways that target the cytoplasmic domain of integrins. A comparison of {alpha}4β1 activity on eosinophils and the Jurkat T lymphocytic cell line suggests that {alpha}4β1 on eosinophils is tightly controlled. That is, the 15/7, HUTS-21, or 9EG7 activation-sensitive antibodies do not react with β1 of purified blood eosinophils using identical protocols, in which the antibodies react robustly with β1 of Jurkat cells [28 , 30 ], indicating that β1 of Jurkat cells is in a higher activation state in comparison with eosinophils. Thus, purified blood eosinophils do not adhere or migrate on the {alpha}4β1 ligand, fibronectin [28 , 58 ], whereas Jurkat cells constitutively adhere to fibronectin [28 ] and migrate on surfaces coated with fibronectin in response to serum (our unpublished results). Coating of Transwell membranes with fibronectin inhibits fMLP-stimulated migration of eosinophils in comparison with uncoated membranes, indicating that fibronectin may even be inhibitory to eosinophil migration [58 ]. Adhesion and migration on fibronectin, therefore, require a highly active form of {alpha}4β1 that is not present on purified blood eosinophils. "Forcing" β1 into a high activation state by incubation of blood eosinophils with the 8A2-activating antibody to β1 results in adherent eosinophils that roll less well on VCAM-1 [27 ], stimulates eosinophil adhesion to fibronectin [28 ], and decreases migration of eosinophils across monolayers of HUVECs [59 ]. Incubation of purified eosinophils from blood of allergic subjects with Mn2+ exposes the activation-sensitive epitope in the β1 hybrid domain recognized by mAb 15/7 [60 ] and enhances adhesion to VCAM-1 [61 ]. RANTES, MCP-3, and eotaxin transiently increase eosinophil interaction with VCAM-1 and with Leu-Asp-Val (LDV)-containing peptide [62 , 63 ]. Thus, steps in eosinophil recruitment mediated by {alpha}4β1 are regulated dynamically by the allosteric structure of {alpha}4β1 present on the eosinophil surface.

Conformations of β1 of eosinophils
We have used conformation-sensitive antibodies to probe β1 conformation on purified or nonpurified blood or airway eosinophils in segmental antigen challenge or steroid withdrawal clinical models of allergic human asthma. Figure 3 depicts a model in which several states of β1 activation are queried with three conformation-sensitive antibodies: N29, HUTS-21, and 9EG7. N29 recognizes an activation-induced epitope in the N-terminal region of the PSI domain [65 ], HUTS-21 recognizes an activation-induced epitope in the hybrid domain [66 ], which is also recognized by mAb 15/7 [60 , 67 ], and 9EG7 recognizes an activation-induced epitope in the EGF domains of the "leg" [68 , 69 ]. The locations of these epitopes in various structures adopted by β1, based on structures of {alpha}Vβ3 and {alpha}IIbβ3, deduced from X-ray crystallographic and electron microscopic studies [24 , 70 ], suggest that the antibodies recognize increasingly activated forms in the order N29 < HUTS-21 < 9EG7. We have found that N29 but not HUTS-21 or 9EG7 recognizes purified blood and airway eosinophils [31 ]. Such eosinophils adhere to immobilized VCAM-1 and not fibronectin [31 ], indicating that the N29+/HUTS-21–/9EG7– putative form of {alpha}4β1, depicted in the middle of Figure 3 , recognizes VCAM-1 but not fibronectin. Jurkat cells, which express the N29+/HUTS-21+/9EG7+ putative form of {alpha}4β1, depicted to the right in Figure 3 , react highly with all three antibodies [30 ], adhere to fibronectin [71 ], and adhere even better to VCAM-1 compared with eosinophils [30 ]. Thus, N29+/HUTS-21–/9EG7– and N29+/HUTS-21+/9EG7+ forms of {alpha}4β1 prefer VCAM-1 over fibronectin. Eosinophils that are purified from blood are more reactive to N29 compared with nonpurified eosinophils in whole blood from the same donor, indicating that β1 is susceptible to activation during the purification procedure [72 ]. In asthmatics with a dual-response phenotype, N29 reactivity of unfractionated blood and bronchoalveolar lavage (BAL) eosinophils, 48 h after segmental antigen challenge, is increased compared with blood eosinophils before challenge (our unpublished results). Moreover, N29 reactivity of BAL eosinophils correlates with the percentage of eosinophils in BAL fluid. These results indicate that the N29-immunoreactive form of β1 is likely important in movement of primed blood eosinophils out of the circulation and into the airway in response to segmental antigen challenge. Indeed, we speculate that VCAM-1 may not be recognized by the N29–/HUTS-21–/9EG7– putative form of {alpha}4β1, illustrated to the left in Figure 3 .


Figure 3
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  		Figure 3. Antibody probes of {alpha}4β1 conformation and affinity. Schematic of three putative conformations of {alpha}4β1 that might be expressed by eosinophils as modeled on the crystal structures of {alpha}Vβ3 and {alpha}IIbβ3 and adapted from Luo and Springer [64 ]. The bent, closed form of {alpha}4β1 is presumably not recognized by any of the activation-sensitive antibodies (left). Extension of {alpha}4β1 reveals the epitope in the β1 plexin, semaphorin, and integrin (PSI) domain recognized by N29; this conformation is presumed to depict most closely the conformation of {alpha}4β1 of blood or airway eosinophils (middle). Further activation results in swing-out of the hybrid domain and exposure of the epitope recognized by HUTS-21, along with separation of the integrin legs and exposure of the epitope recognized by 9EG7 (right). The latter form of {alpha}4β1 is presumably present on Jurkat, EoL-3, or Mn2+- or PMA-activated AML14.3D10 eosinophilic cells [30 ]. TM, Transmembrane; I-EGF, integrin epidermal growth factor domain; βTD, β tail domain.

Based on the use of N29 as a measure for activation of {alpha}4β1 in the antigen-challenge model, N29 positivity of blood eosinophils was assayed in the inhaled corticosteroid (ICS) withdrawal model of controlled elicitation of asthma. In the ICS model, mild asthmatics undergo true or sham ICS withdrawal in a randomized, placebo-controlled, two-period, crossover study. ICS withdrawal results in a decrease in the forced expiratory volume in 1 s (FEV1) [73 ], an increase in circulating and sputum eosinophils [73 ], and a higher percentage of VCAM-1-positive vessels in comparison with subjects before withdrawal [32 ]. We found that N29 epitope expression, which was quantified by flow cytometry on eosinophils in whole blood, correlated inversely with FEV1 after ICS withdrawal and throughout the ICS study [72 ]. In response to ICS withdrawal, N29 epitope expression correlated with fraction of exhaled NO (FENO) [72 ], an established asthma marker and indicator of airway inflammation [74 , 75 ]. Indeed, receiver-operator characteristic curve analysis [76 ] indicates that N29 reactivity is a better predictor of FEV1 <95% of baseline than FENO or sputum eosinophils [72 ]. The ICS study may be the first demonstrated example in which clinical measurements of a disease are predicted by and/or correlate with the activation state of a particular integrin subunit expressed on a circulating cell type.

{alpha}4β1 recognition of VCAM-1 modules
The allosteric, structural forms assumed by {alpha}4β1 of eosinophils in antigen challenge and ICS withdrawal models of asthma are important in the recognition of VCAM-1 modules and alternatively spliced VCAM-1 forms. Shown in Figure 2 , the loop between β strands C and D in the first Ig-like module of VCAM-1 is accessible on the protein surface and contains the core integrin-recognition sequence IDSPL [33 , 77 78 79 80 ]. A second IDSPL site is present in the CD loop in module 4 [78 , 79 ]. Alternative splicing of mRNA encoding VCAM-1 generates two protein forms in humans: a variant consisting of seven Ig-like modules, 7d-VCAM-1, containing putative integrin-binding sites in modules 1 and 4, and a variant containing six Ig-like modules, 6d-VCAM-1, which is missing the putative integrin-binding site in module 4 and contains only the site in module 1 [34 ]. Endothelial cells appear to express more 7d-VCAM-1 compared with 6d-VCAM-1 based on quantitation of mRNA from HUVECs treated with TNF-{alpha} [34 ]. The distance of module 1 from the endothelial surface may be expected to facilitate {alpha}4β1-mediated eosinophil capture from the circulation. That is to say, module 1 of 7d-VCAM-1 may extend 3.7 nm further from the endothelial surface than module 1 of 6d-VCAM-1 or 11.1 nm further than module 4, based on the length of individual, Ig-like modules calculated from rotary-shadowing electron microscopic images of recombinant, soluble 7d-VCAM-1 adsorbed to mica [80 ]. The first two N-terminal modules of 7d-VCAM-1 can mediate rolling and firm adhesion of blood eosinophils via {alpha}4β1 [27 ], indicating that this extension allows ready interaction with eosinophil {alpha}4β1. By studying a set of recombinant forms of VCAM-1, we have shown that {alpha}4β1 mediates robust adhesion of purified blood eosinophils to constructs containing module 1, including 6d-VCAM-1, 7d-VCAM-1, and the construct containing only modules 1–3, 1–3VCAM-1, whereas there is less adhesion mediated by {alpha}4β1 to the construct containing only modules 4–7, 4–7VCAM-1 [30 ]. Thus, purified blood eosinophils recognize module 1 more readily in comparison with module 4 of VCAM-1. Although module 1 may promote the initial capture of eosinophils, the close proximity of module 4 to the endothelial wall may help strengthen adhesion and facilitate movement of activated blood eosinophils out of the circulation. Static adhesion to module 4 of eosinophils or eosinophilic cell lines can be enhanced following incubation with IL-5, Mn2+, or PMA [30 ]. That 7d-VCAM-1 is divalent may be of additional consequence for {alpha}4β1-mediated eosinophil diapedesis. In other words, it may be that modules 1 and 4 of a single VCAM-1 molecule can be ligated simultaneously by two different {alpha}4β1 integrin molecules coexpressed on an individual eosinophil cell. The head of {alpha}4β1, if modeled after the crystal structure of {alpha}Vβ3, has dimensions between 4.5 and 9.0 nm [70 ], smaller than the distance that bridges modules 1 and 4 [80 ]. Structural variations between modules 2 and 5 may orient modules 1 and 4, respectively, differentially for recognition by {alpha}4β1 of eosinophils. That is, although module 2 of VCAM-1 is disulfide-bonded in the crystal structure shown in Figure 2 [33 ], module 5 is unusual for Ig-like modules in lacking such a bond based on proteolysis studies with endoproteinase Glu-C [81 ]. Of note, EoL-3 and AML14.3D10 eosinophilic leukemic cell lines do not recognize module 4 of VCAM-1, although these cells express more surface {alpha}4β1 and display a more conformationally active form of β1 that is better recognized by N29, HUTS-21, and 9EG7 [30 ]. Recognition of modules 1 and 4 by eosinophils is, therefore, controlled by more than the {alpha}4β1 expression level and activation state alone. The β1 subunit of eosinophils but not of eosinophilic cell lines is in podosomes [55 ], which may partly explain the differences between the cell lines and eosinophils. Experiments described below indicate a role for {alpha}Mβ2 as well in eosinophil recognition of VCAM-1 module 4.

{alpha}Mβ2 (CD11b/18, Mac-1)
{alpha}Mβ2 is present on purified blood eosinophils in a conformational state that is constitutively less active than {alpha}4β1. {alpha}Mβ2 of unstimulated, purified blood eosinophils, mediates low levels of static adhesion to module 4 of 7d-VCAM-1 [30 ]. Baseline interaction is regulated by PI-3K, inasmuch as adhesion to module 4 and not module 1 of 7d-VCAM-1 is blocked completely by wortmannin or LY294002 [30 ], both known to block {alpha}Mβ2 integrin-mediated adhesion of eosinophils to ICAM-1 or albumin in response to IL-5 [82 , 83 ]. That inhibitors specific for {alpha}Mβ2 block adhesion to module 4 completely, even though the recognition is partly {alpha}4β1-dependent [30 ], raises the possibility of integrin cross-talk and/or cooperativity between {alpha}Mβ2 and {alpha}4β1. Further evidence that recognition of module 4 by {alpha}Mβ2 is significant comes from the AML14.3D10 and EoL-3 eosinophilic cell lines, which do not express {alpha}Mβ2 and do not adhere to module 4 [30 ].

Whereas {alpha}4β1 of blood eosinophils constitutively ligates VCAM-1, even in the absence of stimulation by cytokines and irrespective of inside-out signaling, {alpha}Mβ2 recognition is influenced greatly by activation. Incubation with IL-5 enhances {alpha}Mβ2-mediated static adhesion of blood eosinophils to ICAM-1 or modules 1 or 4 of VCAM-1 [30 , 82 , 83 ]. The {alpha}Mβ2-mediated adhesion of IL-5-stimulated eosinophils to modules 1 or 4 of VCAM-1 is mostly refractory to inhibition by wortmannin or LY294002 [30 ]. Adhesion of IL-5-stimulated eosinophils to ICAM-1 or albumin is, however, blocked by these inhibitors [82 , 83 ]. Thus, recognition of diverse ligands by {alpha}Mβ2 of eosinophils is differentially regulated. Indeed, under assay conditions that mimic blood flow, IL-5 incubation has the paradoxical effect of decreasing, rather than increasing, adhesion of blood eosinophils to 7d-VCAM-1 in the parallel plate flow chamber within minutes [30 ]. The decrease in adhesion is dependent on {alpha}Mβ2, as it can be reversed by an anti-{alpha}M antibody [30 ]. Such a finding is consistent with the observation that IL-5 promotes the release in vivo of eosinophils from bone marrow via a mechanism that is dependent on β2 integrins and PI-3K and can be inhibited by wortmannin [84 ]. The release of eosinophils may be facilitated further by L-selectin shedding from the surface of eosinophils in response to IL-5 stimulation [85 ]. These results suggest that the recognition of VCAM-1 by {alpha}Mβ2 may be tightly controlled by IL-5. Namely, the IL-5-induced conformation of {alpha}Mβ2 may transiently enhance and then inhibit eosinophil adhesion in a process that may depend on {alpha}Mβ2 activation and be associated with L-selectin shedding. The consequence of such release would be to promote the subsequent movement of eosinophils through the vascular wall into the airway lumen. In support of this conjecture, we have shown that airway eosinophils purified following segmental antigen challenge express a conformationally active form of {alpha}Mβ2 recognized by the CBRM1/5 anti-{alpha}M conformation-sensitive antibody [31 ]. Figure 4 depicts the epitope in the I-domain of the {alpha}M subunit recognized by CBRM1/5 [86 ]. Two different structures believed to represent the inactive or active form of the {alpha}M I-domain have been crystallized in buffers containing manganese or magnesium, respectively [87 , 88 ]. Although the CBRM1/5 epitope is exposed in the presumed inactive crystal form, the epitope is not well recognized by CBRM1/5 [86 ]. Thus, the I-domain of {alpha}M likely undergoes a change in shape or conformation upon activation that facilitates better recognition of the I-domain by CBRM1/5 [86 , 89 ]. As such, the enhanced reactivity of CBRM1/5 of airway compared with blood eosinophils indicates that the {alpha}M I-domain of airway eosinophils is structurally different. Such airway eosinophils recognized by CBRM1/5 adhere to diverse ligands, including VCAM-1, albumin, ICAM-1, fibrinogen, and vitronectin via {alpha}Mβ2 [31 ]. That is to say, a prominent characteristic of {alpha}Mβ2 is its ability to recognize a plethora of structurally diverse ligands and ECM proteins through the Lys245-Arg261 segment of the {alpha}M I-domain [90 ]. Blood eosinophils purified before or after antigen challenge are not well recognized by CBRM1/5 and exhibit little or no adhesion to such ligands [31 ]. Intranasal administration of IL-5, a regulator of {alpha}Mβ2, causes eosinophil migration into the airway lumen of mice [91 ]. This movement is blocked by i.p. administration of the p85a dominant-negative form of the PI-3K regulatory subunit fused to HIV-transactivator of transcription (HIV-TAT) [91 ]. {alpha}Mβ2 expression is up-regulated on human or mouse airway eosinophils following antigen challenge in comparison with blood eosinophils [92 93 94 95 ]. Elevation of {alpha}Mβ2 has also been observed on migratory human blood eosinophils [51 ]. The up-regulation of {alpha}Mβ2 on eosinophils can be achieved following incubation of blood eosinophils with IL-5, GM-CSF, fMLP, or platelet activating factor (PAF) [93 , 96 ]. Expression of {alpha}M on blood eosinophils is increased following incubation with calcium ionophore or after only minutes of PMA stimulation, indicating that blood eosinophils have preformed stores of {alpha}Mβ2 that can be mobilized rapidly to the cell surface [21 ].


Figure 4
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  		Figure 4. I-domain of {alpha}Mβ2. Schematic (left) of the I-domain of {alpha}Mβ2 color-coded to match the crystal structure (right) [87 ]. {alpha}-Helices-1, -3, and -7 of the I-domain (shown in green) undergo conformational changes in response to {alpha}Mβ2 activation [86 ]. Residues recognized by CBRM1/5 are labeled and highlighted in black. The figure was created with PyMol.

Transendothelial migration of eosinophils triggered by eotaxin is inhibited by anti-{alpha}M [51 ]. The chemokines RANTES, MCP-3, and complement (C)5a expose the CBRM1/5 activation epitope of {alpha}Mβ2 [62 , 97 ] and promote migration of blood eosinophils [62 , 97 98 99 100 ]. Treatment with IL-5 exposes the CBRM1/5 epitope of blood eosinophils and mimics the phenotype of airway eosinophils by inducing {alpha}Mβ2-mediated adhesion of blood eosinophils to ICAM-1, albumin, vitronectin, and fibrinogen [31 , 101 ]. IL-5 is up-regulated in the blood and airway of human asthmatics [102 103 104 105 ], and the IL-5R is down-regulated on airway eosinophils compared with blood eosinophils, an indication that the IL-5R on airway eosinophils has been occupied [106 ]. Degranulation of eosinophils stimulated by GM-CSF and PAF is mediated by {alpha}Mβ2 [107 ]. Therefore, up-regulation and activation of {alpha}Mβ2 appear to represent a major and long-lasting consequence of exposure of eosinophils to mediators of eosinophilic inflammation.

{alpha}Dβ2 (CD11d/18)
The {alpha}D and {alpha}M I-domains share 60% amino acid sequence identity [108 ]. As such, {alpha}Dβ2 on eosinophils may be expected to resemble {alpha}Mβ2 in the promiscuous recognition of several ligands. In {alpha}Dβ2-transfected human embryo kidney 293 or IC-21 macrophage cells, {alpha}Dβ2 mediates adhesion to fibrinogen, vitronectin, VCAM-1, or fibronectin and migration on vitronectin [108 ]. In unstimulated or IL-5-treated, purified blood eosinophils, {alpha}Dβ2 has been reported to contribute to adhesion on VCAM-1 in static or flow conditions [21 , 109 ]. Like {alpha}M, airway eosinophils express higher levels of {alpha}D in comparison with blood eosinophils [21 , 31 ], and expression of {alpha}D on blood eosinophils is increased to a level similar to the expression on airway eosinophils following minutes of treatment with PMA and calcium ionophore or 3 days of culture in IL-5 [21 , 109 ]. Eosinophils that are purified from blood express elevated surface levels of {alpha}D compared with eosinophils in whole blood from the same donor, indicating that up-regulation of {alpha}Dβ2, like activation of β1 integrins [72 ], is a consequence of eosinophil activation during purification [72 ]. Thus, as with {alpha}Mβ2, eosinophils appear to have preformed stores of {alpha}Dβ2 that can be mobilized rapidly. We have found that {alpha}D stains diffusely in unstimulated blood eosinophils adherent to VCAM-1 but is present in structures in the substrate plane in airway eosinophils or PMA-activated blood eosinophils adherent to VCAM-1 [55 ]. These {alpha}D-positive structures do not colocalize with podosomes, raising the possibility that {alpha}Dβ2 recognizes VCAM-1 independently of recognition by {alpha}4β1. We have not observed {alpha}D-dependent adhesion of unstimulated or IL-5-stimulated, purified blood eosinophils to VCAM-1 using anti-{alpha}D antibodies but do not exclude the possibility that {alpha}D, like {alpha}M, contributes to eosinophil recognition of VCAM-1 [30 ].

{alpha}4β7 (CD49d/β7)
{alpha}4β7 of blood eosinophils supports static adhesion on MAdCAM-1 and mediates rolling on MAdCAM-1 and VCAM-1 under flow [27 ]. Incubation with PAF induces elevated static adhesion of eosinophils to MAdCAM-1 via {alpha}4β7 [29 ]. Cross-linking of β7 on blood eosinophils by soluble VCAM-1 or Fib 30 antibody increases GM-CSF mRNA expression and survival of blood eosinophils, indicating that {alpha}4β7 is a regulator of eosinophil survival [110 ]. The increased survival is blocked by anti-GM-CSF but not by antibodies to IL-3 or IL-5, pointing to GM-CSF synthesis as the likely target by which ligation of {alpha}4β7 increases viability [110 ].

{alpha}6β1 (CD49f/29)
{alpha}6β1 is a well-known receptor for laminins. {alpha}6β1 supports adhesion of eosinophils purified from allergic donors to human laminin obtained from pepsin digestion of placenta, and eosinophils purified from nonallergic donors adhere less well [23 ]. We did not find specific adhesion of blood eosinophils purified from normal, allergic, or asthmatic subjects or of airway eosinophils to mouse laminin-1, raising the question of if, when, and/or how eosinophils are able to recognize laminin [31 ]. Eosinophil migration through Matrigel, a basement membrane mix that contains laminin-1, is reduced in response to anti-β1 [111 ].

{alpha}Lβ2 (CD11a/18) and {alpha}Xβ2 (CD11c/18)
{alpha}Lβ2 is mostly selective for ICAMs and has a narrower ligand-binding specificity than {alpha}Mβ2 or {alpha}Dβ2 [112 ]. In vitro transendothelial chemotaxis of eosinophils to eotaxin is partly inhibited by anti-{alpha}L [51 ]. {alpha}Xβ2 shares ligands with {alpha}Mβ2 [113 ]. There is little, if any, known about the role of {alpha}Xβ2 on eosinophils, making {alpha}Xβ2 the most enigmatic of integrin heterodimers expressed by eosinophils. We have found no inhibition of blood or airway eosinophil adhesion to ICAM-1, albumin, or fibrinogen by antibodies to {alpha}Lβ2 or {alpha}Xβ2, indicating that these two integrins are inactive on eosinophils for these particular ligands compared with {alpha}Mβ2 [31 ].


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SUMMARY OF EOSINOPHIL INTEGRINS
 
The unique set of integrin heterodimers expressed by eosinophils mediates diverse functions of eosinophil rolling, firm adhesion, migration, respiratory burst, degranulation, and viability. In asthma, these functions are important in orchestrating interactions of eosinophils with ligands expressed by airway cells. {alpha}4β1 and {alpha}Mβ2 are likely the two most important integrins that mediate eosinophil adhesion and movement. These two integrin heterodimers differ in several respects. {alpha}4β1 of unstimulated blood eosinophils mediates rolling along VCAM-1-expressing airway endothelium and constitutively ligates modules 1 and 4 of VCAM-1, whereas {alpha}Mβ2 is constitutively less active and primarily recognizes only module 4 of VCAM-1. {alpha}4β1 in the blood and {alpha}Mβ2 en route to or within the airway can undergo activation. We propose that {alpha}4β1 and {alpha}Mβ2 may cooperate to mediate adhesion and release from luminal ligands, such as VCAM-1, followed by adhesion to and movement on diverse pericellular endothelial ligands mediated by activated {alpha}Mβ2. Specifically, {alpha}4β1, expressed on circulating eosinophils, may undergo activation, i.e., in response to allergen, allowing {alpha}4β1 to better recognize module 1 of 7d-VCAM-1 or 6d-VCAM-1. Following eosinophil capture on endothelium, {alpha}4β1 and {alpha}Mβ2 coexpressed on the eosinophil may compete for binding of module 4 of the aforementioned 7d-VCAM-1 molecule to facilitate firm adhesion. Subsequent activation of {alpha}Mβ2 by IL-5 or chemokines may cause {alpha}Mβ2 to assume a dominant role in recognition of module 4 and a significant role in recognition of module 1. Such recognition may involve a transient increase in adhesion to VCAM-1 mediated by {alpha}Mβ2, followed by release from VCAM-1 of {alpha}Mβ2 within minutes under flow in the presence of IL-5 and release of {alpha}4β1 as a result of possible proteolysis in podosomes [55 ]. The consequence of such release may be to promote {alpha}Mβ2-mediated movement of eosinophils on diverse endothelial ligands in transit to the airway. In essence, movement through airway endothelium may, therefore, involve a "hand-off," whereby {alpha}Mβ2 replaces {alpha}4β1 as the principal adhesive and migratory integrin. The hand-off may be facilitated by IL-5 and/or chemokines including members of the eotaxin family, which can shift integrin use away from {alpha}4β1 to β2 integrins [114 ]. In fact, IL-5 can even inhibit binding of the 15/7 anti-β1 conformation-sensitive antibody to eosinophils from allergic donors [61 ] and as noted, induce L-selectin shedding and release from endothelial selectins. 6d-VCAM-1 with one integrin recognition module and 7d-VCAM-1 with two may regulate differentially such recruitment by virtue of valency of the splice form, distance of the integrin-binding site from the endothelial surface, and/or role of module 4. Activation of {alpha}Mβ2 and diapedesis to the pulmonary vasculature may be facilitated further by degradation of matrix proteins by metalloproteinases in podosomes, transient adhesive structures of IL-5- and TNF-{alpha}-activated blood eosinophils or airway eosinophils.

The remaining five integrins of eosinophils—{alpha}Dβ2, {alpha}4β7, {alpha}6β1, {alpha}Lβ2, and {alpha}Xβ2—likely play supportive roles to {alpha}4β1 and {alpha}Mβ2 in eosinophil recruitment. {alpha}Dβ2 and {alpha}Xβ2 of activated eosinophils potentially recognize VCAM-1 and additional ligands similar to those recognized by {alpha}Mβ2. The enhanced survival of eosinophils in the airway lumen may involve ligation of {alpha}4β7 to soluble, adhesive ligands such as fibronectin. {alpha}6β1 of migrating eosinophils may interact with laminin in transit through a vascular basement membrane, and {alpha}Lβ2 potentially ligates ICAMs. The functions of {alpha}Dβ2, {alpha}4β7, {alpha}6β1, {alpha}Lβ2, and {alpha}Xβ2 of eosinophils, however, warrant further exploration.


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TARGETING EOSINOPHIL INTEGRINS IN VIVO
 
Several competitive inhibitors that target integrin heterodimers have been devised to interfere with the recruitment or number of eosinophils in the asthmatic airway and thus, diminish airway eosinophilic inflammation and particular aspects of asthma, to which eosinophils are thought to contribute [115 ]. These therapies have been evaluated in clinical human trials and diverse animal models including primate, guinea pig, sheep, rabbit, mouse, and rat. Enigmatically, as elaborated below, the studies in humans and in animal models have reached different conclusions.

Most therapeutic strategies involving integrins of eosinophils have targeted {alpha}4, the common subunit of {alpha}4β1, the most important counter-receptor of eosinophils recognizing VCAM-1, and {alpha}4β7, potentially important in recognition of MAdCAM-1. The use of {alpha}4 subunit antagonists as therapeutic agents in clinical disease was first realized with the development of Antegren (Tysabri, Natalizumab), a humanized anti-{alpha}4 antibody that has shown effectiveness in clinical trials for multiple sclerosis and Crohn’s disease [116 ]. In parallel, a number of small molecule inhibitors including BIO-1211 (compound 28) have been developed. BIO-1211 has a 200-fold greater selectivity for the active compared with inactive form of {alpha}4β1 and is based on the LDV sequence from the alternatively spliced, connecting segment-1 (CS-1) peptide of cellular fibronectin [117 , 118 ]. Despite promising results in animal models of asthma, development of BIO-1211 was discontinued as a result of lack of efficacy in phase II clinical trials of asthma conducted by Merck (Rahway, NJ, USA) and Biogen (Cambridge, MA, USA) [119 ]. In preliminary studies, a second LDV mimetic modeled after BIO-1211, IVL745, caused only a modest reduction in sputum eosinophils in human patients with mild-to-moderate, atopic asthma following inhalation and had no effect on the early or late asthmatic response to inhaled allergen or markers of airway inflammation [120 ]. The futures of IVL745 and another {alpha}4β1 antagonist, compound HMR 1031, under investigation by Sanofi-Aventis (France), in phase II trials of asthma, are unclear [119 , 121 ]. HMR 1031 is a potent {alpha}4β1 small molecule antagonist that selectively blocks binding of {alpha}4β1 to VCAM-1 and fibronectin [122 ]. When administered by aerosol for 8 days to patients with mild-to-moderate, persistent asthma, HMR 1031 failed to relieve house dust mite- or methacholine-induced airway eosinophilia, exhaled NO production, or soluble markers of airway hyper-responsiveness [123 ]. Tanabe Seiyaku (Japan)/GlaxoSmithKline (UK) and Roche (Indianapolis, IN, USA) examined in clinical trials two orally active, dual {alpha}4β1/{alpha}4β7 antagonists, TR14035 and R411, respectively [119 ]. TR14035 is no longer listed in GlaxoSmithKline’s therapeutic pipeline [119 ], R411 was discontinued as noted on Roche’s 2006 annual investor report [124 ], and several other {alpha}4β1 antagonists, including GW-559090 from GlaxoSmithKline [125 , 126 ] or RBx-7796 (Clafrinast) from Ranbaxy (India), are no longer listed in either company’s pipeline.

The relative failure of {alpha}4 antagonists in humans is puzzling, given the effectiveness of these compounds in animal models of asthma. Thus, although described above, BIO-1211, HMR 1031, IVL745, TR14035, or GW559090 {alpha}4β1 antagonists have negligible benefit in human asthma clinical trials, these compounds have had significant effects in sheep [120 , 123 , 127 ], mouse [123 , 128 ], rat [120 , 125 , 129 ], or guinea pig [125 ] models of asthma. The HP1/2, PS2/3, PS/2, TA-2, or Max-68P anti-{alpha}4-blocking antibodies, CS-1 peptide ligand anti-{alpha}4β1 mimic, or {alpha}4β1 small molecule inhibitors reduce numbers of eosinophils in the airway or ameliorate inflammatory histopathology or airway allergic responses in the guinea pig [130 131 132 133 134 ], sheep [135 136 137 138 ], mouse [139 140 141 ], rat [142 , 143 ], or rabbit [144 ]. A limitation of such studies is the failure to differentiate among effects resulting from eosinophils, roles of integrins of eosinophils, or roles of other cell types [145 146 147 148 ]. Of additional consequence, there are reports of cellular movement independent of β1 or β2 integrins in a model of T cell migration within a three-dimensional collagen gel [149 ] or by granulocytes null for β2 in response to fMLP [151 ], suggesting that movement of eosinophils or leukocytes in disease may involve processes other than or in addition to integrins. In any case, more informative models of inflammation that are better able to define the specific role of integrins of eosinophils in asthma and disease may result in improved therapeutic outcome.

Approaches that target integrins in eosinophil-associated diseases, including asthma, likely can be improved significantly. One problem in the development of such inhibitors may be the functional overlap and redundancy of integrins. In other words, {alpha}4β1, {alpha}Lβ2, and {alpha}Mβ2 may be able to compensate for one another to some extent in vivo [151 152 153 ]. Thus, simultaneous targeting of several integrins may be a potentially more advantageous strategy than antagonizing only one integrin molecule. Indeed, the success of corticosteroids or β2-adrenergic receptor agonists (bronchodilators) in dampening airway inflammation could be said to result from such broad activity on several inflammatory targets at once [121 ]. Nonetheless, morbidity and mortality continue to increase in eosinophil-related diseases, including asthma, despite the availability of corticosteroids formulated for delivery to the lung [154 ]. Clearly, there is a need for additional therapies that inhibit eosinophilic inflammation. Therapies that broadly target integrins would offer the possibility of potently suppressing eosinophil-related pathologies with greater specificity and with lesser side-effects compared with current treatments. Such therapy could target recruitment mechanisms involving {alpha}4 and β2 integrins. This strategy may prove efficacious against neutrophils as well as eosinophils and be of use in subjects with severe or persistent asthma with predominantly neutrophilic inflammation [155 156 157 ]. As noted previously, β2 integrins of human eosinophils recognize VCAM-1 and numerous matrix proteins of the pulmonary vasculature, mediate adhesion and movement of eosinophils, and are regulated by PI-3K, a target of therapeutic value in the murine asthma model [91 ]. Movement of human eosinophils is antagonized by anti-β2 [57 , 158 159 160 161 ]. In fact, such migration is inhibited even more effectively with a combination of anti-{alpha}4 and anti-β2 than either alone [162 ]. Several models of allergic inflammation in animals indicate that β2 integrins may be promising therapeutic targets in future treatment regimens of asthma [143 , 144 ]. A major worry is immunosuppression arising from antagonism of β2 integrins. An example is efalizumab (Raptiva®, Genentech, San Francisco, CA, USA), a humanized, anti-{alpha}L mAb that has been approved for the treatment of psoriasis [162 ]. Efalizumab has shown moderate efficacy in reducing accumulation of eosinophils in the airway and in attenuating the late asthmatic response of human subjects with atopic asthma [163 ]. Efalizumab is immunosuppressive and may, therefore, be contra-indicated in patients with infection, who are already immunocompromised or who are pregnant [162 ]. One strategy to improve integrin antagonists, such as efalizumab, may be to develop inhibitors that bind only certain integrin activation states. Targeting specific structural conformers of integrins, in turn, may block only certain integrin-ligand interactions and minimize side-effects.

Received June 3, 2007; revised August 17, 2007; accepted August 18, 2007.


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