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Osteopontin Enhances Phagocytosis through a Novel Osteopontin Receptor, the _Xβ₂ Integrin¹

Lotte Schack^*,,, Romualdas Stapulionis^*,,, Brian Christensen, Emil Kofod-Olsen^*, Uffe B. Skov Sørensen^*, Thomas Vorup-Jensen^*,, Esben S. Sørensen^, and Per Höllsberg^2,*

^* Department of Medical Microbiology and Immunology and Department of Molecular Biology, Interdisciplinary Nanoscience Center (iNANO), Institute for Storage Ring Facilities, Aarhus University, Aarhus, Denmark

Osteopontin (OPN) is a cytokine with multiple functions, including immune defense mechanisms against invading microorganisms. OPN-deficient mice are impaired in clearing intracellular pathogens, suggesting an important role of OPN during phagocytosis, but it remains to be defined how OPN may enhance this innate immune process. Here, we demonstrate that OPN binds to monocytes, but not resting T cells, NK cells, or B cells, and mediates chemoattraction of IL-1-activated human monocytes. Moreover, OPN binds in a specific manner to all known serotypes of the two bacterial species Streptococcus agalactiae and Staphylococcus aureus and opsonizes these bacteria for phagocytosis. We identify the integrin _Xβ₂ (CD11c/CD18), which is highly expressed on the cell surface of monocytes, as a novel OPN receptor. To eliminate the contribution from other molecular interactions between the bacteria and the phagocyte, we show that OPN-coated synthetic beads are phagocytosed in an _Xβ₂ integrin-dependent manner. The ligand recognition does not involve the RGD motif previously reported to support binding of OPN to integrins. Taken together, these data identify the _Xβ₂ integrin as a novel OPN receptor that is required for OPN-mediated phagocytosis, thereby elucidating an important mechanism of an innate immune function of OPN.

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.

¹ This work was supported by grants from the Danish Dairy Research Foundation, Arla Foods, the Milk Protein Research Consortium, the LEO Pharma Foundation, the Carlsberg Foundation, the Novo Nordisk Foundation, and the Faculty of Health Sciences, Aarhus University.

² Address correspondence and reprint requests to Dr. Per Höllsberg. Department of Medical Microbiology and Immunology, The Bartholin Building, Wilhelm Meyers Allé 4, Aarhus University, DK-8000 Aarhus C, Denmark. E-mail address: ph{at}microbiology.au.dk

³ Abbreviations used in this paper: OPN, osteopontin; MFI, mean fluorescence intensity; MNC, mononuclear cell; OPN*, Alexa Fluor 488-conjugated OPN.

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