More than the sum of the parts: cooperation between leukocyte adhesion receptors during extravasation.

Over the past decade, it has become clear that the specificity and targeted regulation of leukocyte trafficking result from the sequential and frequently overlapping functions of various adhesive receptors. Adhesion between the leukocyte and the vessel wall begins with repeated transient interactions that allow the leukocyte to “roll” across the endothelium at a rate lower than that of blood flow. Rolling is attributed to the interaction between carbohydrate ligands and either members of the selectin family (1, 2) or CD44 (3, 4) and is followed by firm adhesion mediated by receptors of a different class, the leukocyte integrins. These integrins require activation-induced avidity increases to bind their ligands, generally members of the immunoglobulin gene superfamily. The primary relevant integrins expressed by leukocytes contain either α4 (the heterodimers α4β1 and α4β7) or β2, also known as CD18, which heterodimerizes with any of four distinct α chains to form LFA-1, Mac-1, p150,95, and αdβ2 (5). The combination of adhesion receptor expression and microenvironmental influences encountered by leukocytes as they traverse the endothelium controls integrin activation and determines the leukocyte subsets recruited to a particular site and the kinetics with which this recruitment occurs. Loss of any of the adhesion molecules in this scheme could result in reduced extravasation of particular leukocyte subsets at sites of inflammation. Early studies of leukocyte adhesion molecule deficiency 1 disease (LADI), a genetic deficiency in which affected patients are subject to recurrent bacterial and fungal infections and have impaired wound healing, showed mutations in CD18. It is perhaps fitting that the manuscript by Forlow et al. in a recent issue of the JCI (6) focuses in part on the same molecule. Mice lacking all three selectins, the β2 integrins, ICAM-1, or various combinations of these adhesion receptors have been generated with varying outcomes in induced inflammatory models, but generally these strains remain healthy under standard laboratory conditions (7, 8). The earliest indication of a spontaneous inflammatory defect resulting from adhesion receptor gene targeting was seen in mice doubly deficient for E- and P-selectin. Similar to the phenotype reported in the present study, the abnormalities in these mice consist primarily of excoriative skin lesions associated with bacterial colonization in the head and neck (9, 10). Rolling interactions are severely compromised in E/P-selectin–deficient mice, which fail to induce normal inflammatory responses to peritoneal infection with Streptococcus pneumoniae. These studies clearly established rolling as a prerequisite for firm adhesion. The second instance of a spontaneous and severe inflammatory condition was identified in CD18-deficient mice, again consisting primarily of mucocutaneous lesions (11). Nearly all mice of this genotype develop a similar progressive ulcerative dermatitis and are highly susceptible to inoculated S. pneumoniae. Intravital microscopy revealed that firm adhesion but not rolling is markedly impaired in these mice.