Integrin mediated adhesion of eosinophils to VCAM-1 (CD106) and other ligands.

摘要

Recruitment of eosinophils in asthma involves integrins interacting with 7-domain (7d) and 6d splice forms of vascular cell adhesion molecule 1 (VCAM-1. CD106) expressed on airway endothelium. I characterized adhesion to VCAM-1 of eosinophils purified from blood or bronchoalveolar lavage (BAL) fluid following segmental antigen challenge.; Three integrin heterodimeric adhesion receptors are known to interact with VCAM-1: alpha4beta1 (CD49d/29), alphaDbeta2 (alphaD/CD18), and alpha4beta7 (CD49d/beta7). Four other integrins are present on eosinophils: alpha6beta1 (CD49e/29), alphaLbeta2 (CD11a/18), alphaMbeta2 (CD11b/18), and alphaXbeta2 (CD11c/18). Blood eosinophils adhered similarly to recombinant 6d-VCAM-1 and 7d-VCAM-1. Further dissection of' VCAM-1, however, revealed complexities in recognition of module 4, which is missing from 6d-VCAM-1. Antibody blocking and pharmacological inhibition indicated that eosinophil adhesion to 6d-VCAM-1 or a VCAM-1 construct containing modules 1-3 is mediated by alpha4beta1, whereas adhesion to modules 4-7 is mediated by alpha4beta1 and, unexpectedly, alphaMbeta2. IL-5 enhanced adhesion to 6d-VCAM-1, 7d-VCAM-1, or 4-7VCAM-1; enhanced adhesion was blocked by anti-alphaMbeta2.; BAL eosinophils adhered to VCAM-l and, unlike blood eosinophils, to albumin, ICAM-1 (CD54), fibrinogen, and vitronectin. BAL eosinophil adhesion to 7d-VCAM-1 involved a greater alphaMbeta2 component compared to blood eosinophils. Adhesion of BAL eosinophils to albumin, ICAM-1, fibrinogen, and vitronectin was mediated solely by alphaMbeta2. Podosomes, structures believed important in migration, and the activation-induced CBRM1/5 epitope of alphaMbeta2 were increased on BAL eosinophils in comparison to blood eosinophils. IL-5 induced the CBRM1/5 epitope and increased adherence to albumin, ICAM-1, fibrinogen, or vitronectin.; Thrombin cleaved 7d-VCAM-1 in the sequence PGPR/IAAQIGD at the N-terminus of module 4. 6d-VCAM-1 was not cleaved. Thrombin removal of modules 1-3 attenuated eosinophil adhesion to CHO monolavers expressing 7d-VCAM-1.; These results identify novel mechanisms by which eosinophils are recruited to the asthmatic airway. alpha4beta1 interacts with module 1 of VCAM-1, whereas alphaMbeta2 and alpha4beta1 mediate adhesion to module 4. IL-5 enhances alphaMbeta2-mediated adhesion to module 4 and induces alphaMbeta2-mediated adhesion to module 1. The enhanced adhesion is accompanied by increased podosome formation that presumably facilitates movement of eosinophils to the airway in concert with interaction of activated alphaMbeta2 with other ligands. Proteolytic removal of modules 1-3 by thrombin may attenuate recruitment.