Differential Regulation of $\beta $1 and $\beta $2 Integrin Avidity by Chemoattractants in Eosinophils

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 20; pp. 10939 - 10944
• Main Authors: Weber, Christian, Kitayama, Joji, Springer, Timothy A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01.10.1996; National Acad Sciences
• Subjects: Actins; CD18 Antigens - physiology; Cell Adhesion; Chemokine CCL5 - metabolism; Chemokine CCL7; Chemotactic factors; Chemotactic Factors - physiology; Chemotaxis, Leukocyte; Complement C5a - metabolism; Cytokines; Endothelium; Eosinophils; Eosinophils - physiology; Epitopes; Fibronectins - metabolism; Fibrosis; Humans; Integrin alpha4beta1; Integrin beta1 - physiology; Integrins; Integrins - physiology; Isotypes; Ligands; Macrophage-1 Antigen - physiology; Monocyte Chemoattractant Proteins - metabolism; Physiological regulation; Receptors, Lymphocyte Homing - physiology; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.20.10939

The CC chemokines regulated on activation normal T expressed and secreted (RANTES) and monocyte chemotactic protein 3 (MCP-3), and the anaphylatoxin C5a, induce activation, degranulation, chemotaxis, and transendothelial migration of eosinophils. Adhesion assays on purified ligands showed differential regulation of $\beta $1 and $\beta $2 integrin avidity in eosinophils. Adhesiveness of VLA-4 ($\alpha $4$\beta $1, CD29/CD49d) for vascular cell adhesion molecule 1 or fibronectin was rapidly increased but subsequently reduced by RANTES, MCP-3, or C5a. The deactivation of VLA-4 lead to cell detachment, whereas phorbol 12-myristate 13-acetate induced sustained activation of VLA-4. In contrast, chemoattractants stimulated a prolonged increase in the adhesiveness of Mac-1 ($\alpha $M$\beta $2, CD11b/CD18) for intercellular adhesion molecule 1. Inhibition by pertussis toxin confirmed signaling via G protein-coupled receptors. Chemoattractants induced transient, while phorbol 12-myristate 13-acetate induced sustained actin polymerization. Disruption of actin filaments by cytochalasins inhibited increases in avidity of VLA-4 but not of Mac-1. Chemoattractants did not upregulate a Mn$^{2+}$-inducible $\beta $1 neoepitope defined by the mAb 9EG7, but induced prolonged expression of a Mac-1 activation epitope recognized by the mAb CBRM1/5. This mAb inhibited chemoattractant-stimulated adhesion of eosinophils to intercellular adhesion molecule 1. Thus, regulation of VLA-4 was dependent on the actin cytoskeleton, whereas conformational changes appeared to be crucial for activation of Mac-1. To our knowledge, this is the first demonstration that physiological agonists, such as chemoattractants, can differentially regulate the avidity of a $\beta $1 and a $\beta $2 integrin expressed on the same leukocyte.