Role of α₆β₁ integrin in leukocyte adhesion and transmigration

Abstract

Integrins are a family of heterodimeric cell-surface adhesion and signaling molecules each composed of an α and a β subunit. At present 18 α and 8 β subunits have been identified giving rise to 24 distinct integrin molecules. Many members of this family, primarily integrins containing a β₁ subunit, act as receptors for extracellular matrix proteins, e.g., α₁β₁ and α₂β₁ are key receptors for collagen while α₃β₁ and α₆β₁ are key receptors for laminin. The integrin α₆β₁ (VLA-6, CD49f/CD29) was originally identified on platelets but is now known to be expressed on numerous cell types including epithelial and endothelial cells and is indeed the key leukocyte laminin receptor. Its principal functional role relates to regulation of cell adhesion and motility, and, in line with this, α₆β₁ interaction with its ligands leads to cellular cytoskeletal rearrangement and polarization. In the context of inflammatory events, the ability of α₆β₁ to bind vascular laminins has led to much interest in the role of this integrin in regulation of leukocyte migration through the vascular basement membrane (BM). In blood vessels, the BM forms a thin protein sheet that underlies the endothelium and encases the pericytes/smooth muscle cells. Major constituents of this BM are laminins (laminin 8 and laminin 10) and collagen IV, which form two independent networks that are interconnected by molecules such as nidogens (nidogen-1 and nidogen-2) and the large heparan sulfate proteoglycan, perlecan [1]. In contrast to our growing knowledge of the molecules and mechanisms that mediate leukocyte migration through the endothelium [2], less is known about the mechanisms that mediate and regulate leukocyte migration through the vascular BM.