Leukocytes stop rolling and attach firmly to endothelium at sites of inflammation through coordinated activation of leukocyte integrins and endothelial integrin ligands.
Integrins and their activation
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Integrins are transmembrane, two-chain glycoproteins that mediate leukocyte adhesion to endothelium and adhesion of various cells to the extracellular matrix.
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Resting leukocytes express integrins in a low-affinity form that does not bind their specific ligands until chemokines activate the leukocytes.
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Chemokines secreted at inflammatory sites bind endothelial proteoglycans and are displayed at high concentrations on the endothelial surface.
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When rolling leukocytes encounter these chemokines, their integrins undergo conformational changes and cluster together, converting to a high-affinity form.
Endothelial activation and leukocyte arrest
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Tumor necrosis factor (TNF) and IL-1 activate endothelial cells to increase expression of integrin ligands.
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Increased endothelial ligand expression and increased leukocyte integrin affinity together produce firm adhesion at the inflammatory site.
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Integrin engagement delivers signals that cause cytoskeletal changes, arrest leukocyte rolling, and firmly attach leukocytes to endothelium.
Clinical relevance
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Mutations affecting integrins or selectin ligands can impair leukocyte adhesion and inflammation, resulting in recurrent bacterial infections.
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Integrin antagonists are approved for some chronic inflammatory diseases, including multiple sclerosis and inflammatory bowel disease.