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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4492-4502. Prepublished online as a Blood First Edition Paper on September 7, 2007; DOI 10.1182/blood-2007-02-076539.
PHAGOCYTES CD44-mediated phagocytosis induces inside-out activation of complement receptor-3 in murine macrophages1 Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON; 2 Toronto General Hospital Research Institute of the University Health Network, Toronto, ON; 3 Division of Integrative Biology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH; and 4 Research Institute of the Hospital for Sick Children, Toronto, ON
Diverse receptors, including Fc
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
receptors and β2 integrins (complement receptor-3 [CR3], CD11b/CD18), have been implicated in phagocytosis, but their distinct roles and interactions with other receptors in particle engulfment are not well defined. CD44, a transmembrane adhesion molecule involved in binding and metabolism of hyaluronan, may have additional functions in regulation of inflammation and phagocytosis. We have recently reported that CD44 is a fully competent phagocytic receptor that is able to trigger ingestion of large particles by macrophages. Here, we investigated the role of coreceptors and intracellular signaling pathways in modulation of CD44-mediated phagocytosis. Using biotinylated erythrocytes coated with specific antibodies (anti-CD44–coated erythrocytes [Ebabs]) as the phagocytic prey, we determined that CD44-mediated phagocytosis is reduced by 45% by a blocking CD11b antibody. Further, CD44-mediated phagocytosis was substantially (42%) reduced in CD18-null mice. Immunofluorescence microscopy revealed that CD11b is recruited to the phagocytic cup. The mechanism of integrin activation and mobilization involved activation of the GTPase Rap1. CD44-mediated phagocytosis was also sensitive to the extracellular concentration of the divalent cation Mg2+ but not Ca2+. In addition, buffering of intracellular Ca2+ did not affect CD44-mediated phagocytosis. Taken together, these data suggest that CD44 stimulation induces inside-out activation of CR3 through the GTPase Rap1. 
