Regulation of LFA-1-dependent inflammatory cell recruitment by Cb1-b and 14-3-3 proteins

Eun Young Choi, Valeria V. Orlova, Susanna C. Fagerholm, Susanna M. Nurmi, Li Zhang, Christie M. Ballantyne, Carl G. Gahmberg, Triantafyllos Chavakis

    Research output: Contribution to journalArticle

    43 Citations (Scopus)

    Abstract

    Inside-out signaling regulation of the beta 2-integrin leukocyte function-associated antigen-1 (LFA-1) by different cytoplasmic proteins, including 14-3-3 proteins, is essential for adhesion and migration of immune cells. Here, we identify a new pathway for the regulation of LFA-1 activity by Cbl-b, an adapter molecule and ubiquitin ligase that modulates several signaling pathways. Cbl-b-1- mice displayed increased macrophage recruitment in thioglycollate-induced peritonitis, which was attributed to CbI-b deficiency in macrophages, as assessed by bone marrow chimera experiments. In vitro, Cbl-b(-1-) bone marrow-derived mononuclear phagocytes (BMDMs) displayed increased adhesion to endothelial cells. Activation of LFA-1 in Cbl-b-deficient cells was responsible for their increased endothelial adhesion in vitro and peritoneal recruitment in vivo, as the phenotype of Cbl-b deficiency was reversed in Cbl-b(-/-)LFA-1 (-/-) mice. Consistently, LFA-1-mediated adhesion of BMDM to ICAM-1 but not VLA-4-mediated adhesion to VCAM-1 was enhanced by CbI-b deficiency. Cbl-b deficiency resulted in increased phosphorylation of T758 in the beta 2-chain of LFA-1 and thereby in enhanced association of 14-3-30 protein with the beta 2-chain, leading to activation of LFA-1. Consistently, disruption of the 14-3-3/beta 2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b-1- BMDMs. In conclusion, CbI-b deficiency activates LFA-1 and LFA-1-mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 beta-chain and 14-3-3 proteins.

    Original languageEnglish
    Pages (from-to)3607-3614
    Number of pages8
    JournalBlood
    Volume111
    Issue number7
    DOIs
    Publication statusPublished - 1 Apr 2008

    Keywords

    • EXTRACELLULAR ADHERENCE PROTEIN
    • CBL ADAPTER PROTEIN
    • C-CBL
    • NEGATIVE REGULATION
    • CYTOPLASMIC DOMAIN
    • INTEGRIN PHOSPHORYLATION
    • STAPHYLOCOCCUS-AUREUS
    • EFFECTOR MOLECULE
    • UBIQUITIN LIGASES
    • HUMAN NEUTROPHILS

    Cite this

    Choi, E. Y., Orlova, V. V., Fagerholm, S. C., Nurmi, S. M., Zhang, L., Ballantyne, C. M., Gahmberg, C. G., & Chavakis, T. (2008). Regulation of LFA-1-dependent inflammatory cell recruitment by Cb1-b and 14-3-3 proteins. Blood, 111(7), 3607-3614. https://doi.org/10.1182/blood-2007-07-103077