ViewpointThe α4-integrin: an alternative pathway for neutrophil recruitment?
Section snippets
The integrin family of adhesion molecules
The integrins are a family of transmembrane-spanning adhesion molecules expressed on the surface of leukocytes as non-covalent heterodimers. Each functional unit consists of one α and one β chain8. Studies have identified at least 21 different α chains and eight different β chains, which can associate to form heterodimers with different adhesive specificities. These molecules function to mediate adhesive interactions of leukocytes with ligands expressed on the endothelium [intercellular
α4-integrin expression by pharmacological stimuli
Recently, human neutrophils have been shown to express α4-integrins under certain conditions, and to mediate functional adhesive interactions with appropriately activated endothelium and other substrates in vitro15. These data are causing several laboratories to re-examine the possibility that the α4-integrin exists on or within neutrophils. Although the α4-integrin is likely to be at very low levels or non-existent on the surface of unactivated neutrophils (depending upon species),
Expression of the α4-integrin by physiological stimuli
Although the cytochalasins have been a useful tool to demonstrate expression of the α4-integrins, there are more physiological situations in which these molecules are upregulated. Gao and Issekutz17 reported an increase in α4-integrin expression on human neutrophils after stimulation with C5a alone. Although the shift in expression was small, this low level of α4-integrin was able to mediate significant levels of neutrophil migration across monolayers of human synovial, dermal or lung
Neutrophil migration through the extravascular matrix: a role for α4-integrin?
The upregulation of α4-integrin on transmigrated neutrophils might be a response that aids neutrophils in their movements through extravascular tissues (Fig. 1a). Indeed, α4-integrin can mediate CD18-independent adhesion of emigrated neutrophils to cardiac myocytes or intestinal epithelial cells20, 21, and plays a role in neutrophil movement through fibroblast monolayers17, 18. It is known that α4-integrin can bind to the ECM component fibronectin22, and might play a role in neutrophil
Immature neutrophils and α4-integrin
In general, most studies consider circulating neutrophils as a single homogeneous population of cells. This view might not be entirely accurate because immature neutrophils are often present in the circulation during chronic inflammation. This might be relevant because neutrophil precursors express α4-integrin, which is downregulated at some time during terminal differentiation25. It is unclear when α4-integrin disappears from neutrophils, but the promyelocytic cell line HL-60 maintains
Role of α4-integrins in neutrophil recruitment in animal models of inflammation
Using flow cytometry, α4-integrin can be detected constitutively at low levels on rat neutrophils20, 29, 30. Although it does not appear to mediate neutrophil trafficking under baseline conditions in vivo11, or contribute to neutrophil recruitment in response to acute inflammatory mediators such as LTC4 (Ref. 12), the α4-integrin can mediate low-level neutrophil adhesion to purified VCAM-1 and MAdCAM-1 under static adhesion conditions30. Under laminar flow conditions, very few normal rat
Other non-β2-integrin-dependent models
It is intriguing that little attention has been given to alternative adhesion pathways for neutrophils despite the numerous studies36, 37, 38, 39, 40, 41, 42, 43, 44, 45 that have reported β2-integrin-independent recruitment of neutrophils. In the rabbit peritoneum, protease peptone-induced neutrophil migration at 4 h could be inhibited by antibodies against CD18 but not against the α4-integrin36. However, neutrophil infiltration at 24 h could not be blocked by antibodies against either CD18 or
Other roles for α4-integrins
A final consideration is the possibility that the α4-integrins play inflammatory roles that are not linked directly to leukocyte recruitment. For example, intratracheal administration of an anti-α4-integrin antibody has been shown to reduce dysfunction associated with airway hypersensitivity without affecting cellular recruitment46. Whether any part of this protection is the result of the blockade of α4-integrin function on emigrated neutrophils remains to be determined.
Concluding remarks
In summary, this viewpoint article has reviewed evidence that neutrophils can indeed express functional α4-integrins and mediate adhesive interactions with endothelium, purified adhesion molecules, ECM proteins and parenchymal cells. Unlike the β2-integrin-dependent recruitment pathway, which dominates under normal and acute inflammatory conditions (Fig. 1a), α4-integrin and/or other molecules might play roles in mediating neutrophil recruitment in more chronic inflammatory processes (Fig. 1b).
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