alpha-Chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation

Susanna C. Fagerholm, Minna Varis, Michael Stefanidakis, Tiina J. Hilden, Carl G. Gahmberg

    Research output: Contribution to journalArticlepeer-review

    70 Citations (Scopus)

    Abstract

    The promiscuous CD11b/CD18 (Mac-1) integrin has important roles in regulating many immunologic functions such as leukocyte adhesion and emigration from the bloodstream via interactions with the endothelial ligands ICAM-1 and ICAM-2, iC3b-mediated phagocytosis, and apoptosis. However, the mechanisms for Mac-1 inside-out activation have remained poorly understood. Phosphorylation of integrin cytoplasmic domains is emerging as an important mechanism of regulating integrin functions. Here, we have studied phosphorylation of human CD11b, which takes place on the cytoplasmic Ser1126 in neutrophils. We show that mutation of the serine phosphorylation site leads to inability of Mac-1 to become activated to bind the cellular ligands ICAM-1 and ICAM-2. However, CD11b-mutant cells are fully capable of binding other studied CD11b ligands (ie, iC3b and denatured BSA). Activation epitopes expressed in the extracellular domain of the integrin and affinity for soluble ICAM ligands were decreased for the mutated integrin. Additionally, the mutation resulted in inhibition of chemokine-induced migration in a transendothelial assay in vitro and significantly reduced the accumulation of intravenously administered cells in the spleen and lungs of Balb/c mice. These results characterize a novel selective mechanism of Mac-1–integrin activation, which mediates leukocyte emigration from the bloodstream to the tissues.
    Original languageEnglish
    Pages (from-to)3379-3386
    Number of pages8
    JournalBlood
    Volume108
    Issue number10
    DOIs
    Publication statusPublished - Nov 2006

    Keywords

    • CD11b antigen
    • CD18 antigen
    • Intercellular adhesion
    • Leukocyte
    • Phosphorylation

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