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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3607-3614.
Prepublished online as a Blood First Edition Paper on January 31, 2008; DOI 10.1182/blood-2007-07-103077.
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Submitted July 25, 2007
Accepted January 28, 2008
Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-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, and Triantafyllos Chavakis*
Experimental Immunology Branch, NCI, NIH, Bethesda, MD, United States
Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
Division of Biochemistry, Faculty of Biosciences, University of Helsinki, Helsinki, Finland
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, United States
Department of Medicine, Baylor College of Medicine, & Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, TX, United States
* Corresponding author; email: chavakist{at}mail.nih.gov.
Inside-out signaling regulation of the  2-integrin LFA-1 by different cytoplasmic proteins, including 14-3-3 proteins, is essential for adhesion and migration of immune cells. Here we identified 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-/- mice displayed increased macrophage recruitment in thioglycollate-induced peritonitis, which was attributed to Cbl-b deficiency in macrophages, as assessed by bone marrow chimera experiments. In vitro, Cbl-b-/- bone marrow derived mononuclear phagocytes (BMDM) 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 Cbl-b deficiency. Cbl-b-deficiency resulted in increased phosphorylation of T758 in the â2-chain of LFA-1 and thereby in enhanced association of 14-3-3 protein with the 2-chain, leading to activation of LFA-1. Consistently, disruption of the 14-3-3/2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b-/- BMDM. In conclusion, Cbl-b deficiency activates LFA-1 and LFA-1-mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 -chain and 14-3-3 proteins.
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