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J. Biol. Chem., Vol. 278, Issue 46, 45720-45729, November 14, 2003

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Fc-receptors Induce Mac-1 (CD11b/CD18) Mobilization and Accumulation in the Phagocytic Cup for Optimal Phagocytosis^*

Jenny Jongstra-Bilen¶, Rene Harrison¶||, and Sergio Grinstein**

From the Cell Biology Program, Hospital for Sick Children and the Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1X8 and Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network and the Department of Immunology, University of Toronto, Toronto, Ontario M5T 2S8, Canada

Functional interactions between Fc-receptors (FcR) and the ₂ integrin Mac-1 (CD11b/CD18) have been described, but the molecular basis of this relationship remains unclear. Although the glycosylphosphatidylinositol-linked receptor FcRIIIB of human neutrophils is constitutively associated with Mac-1, we found no evidence for direct physical association between Mac-1 and the FcR of mouse macrophages, which are transmembrane proteins. Nevertheless, Mac-1 accumulated in the phagocytic cup following engagement of FcR by IgG-opsonized particles. Blocking the CD18 chains of ₂ integrins by using specific antibodies reduced Mac-1 accumulation in the cup. These antibodies or the addition of the recombinant CD11b I-domain inhibited the ingestion of IgG-opsonized particles. FcR cross-linking stimulated cell adhesion to surfaces coated with Mac-1 ligands and in addition enabled macrophages to bind C3bi-opsonized particles, indicating that FcR-derived signals induce activation of Mac-1. Measurements of fluorescence recovery after photobleaching revealed that whereas most (>80%) of Mac-1 is immobile in resting cells, stimulation of FcR markedly increases the mobile fraction of the integrin. Activation of Mac-1 by FcR required the activity of Src family tyrosine kinases, phosphatidylinositol 3-kinase and phospholipase C, with the release of diacylglycerol and stimulation of protein kinase C. Because elevated cytosolic Ca²⁺ was not required, we suggest that novel protein kinase C isoforms are involved in Mac-1 activation. These results suggest that FcR stimulation promotes Mac-1 clustering into high avidity complexes in phagocytic cups by releasing the integrin from cytoskeletal constraints and enhancing its lateral diffusion. FcR can enhance host defense by activating Mac-1 (and possibly other integrins), having a synergistic effect on pathogen engulfment and promoting the adherence of phagocytes at sites of infection.

Received for publication, April 9, 2003 , and in revised form, August 11, 2003.

^* This work was supported in part by the Canadian Institutes of Health Research and the Canadian Arthritis Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this

^|| Recipient of a RESTRACOMP fellowship from the Hospital for Sick Children.

^** Present holder of the Pitblado Chair in Cell Biology. To whom correspondence should be addressed. Tel.: 416-813-5727; Fax: 416-813-5028; E-mail: sga{at}sickkids.ca.

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