This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kyriakides, T. R. Articles by Bornstein, P. Search for Related Content PubMed PubMed Citation Articles by Kyriakides, T. R. Articles by Bornstein, P.

(American Journal of Pathology. 2004;165:2157-2166.)
© 2004 American Society for Investigative Pathology

The CC Chemokine Ligand, CCL2/MCP1, Participates in Macrophage Fusion and Foreign Body Giant Cell Formation

Themis R. Kyriakides^*, Matt J. Foster^*, Grant E. Keeney^*, Annabel Tsai, Cecilia M. Giachelli, Ian Clark-Lewis, Barrett J. Rollins and Paul Bornstein^*

From the Departments of Biochemistry^* and Bioengineering, University of Washington, Seattle, Washington; the Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada, and the Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

The foreign body reaction (FBR) develops in response to the implantation of almost all biomaterials and can be detrimental to their function. The formation of foreign body giant cells (FBGC), which damage the surface of biomaterials, is considered a hallmark of this reaction. FBGC derive from blood-borne monocytes that enter the implantation site after surgery in response to the release of chemotactic signals. In this study, we implanted biomaterials subcutaneous (s.c.) in mice that lack the monocyte chemoattractant CC chemokine ligand 2 (CCL2) and found that biomaterials were encapsulated despite reduced FBGC formation. The latter was due to compromised macrophage fusion rather than migration. Consistent with the reduction in FBGC formation, biodegradable biomaterials sustained reduced damage in CCL2-null mice. Furthermore, blockade of CCL2 function by localized gene delivery in wild-type mice hindered FBGC formation, despite normal monocyte recruitment. The requirement for CCL2 in fusion was confirmed by the ability of both a CCL2 inhibitory peptide and an anti-CCL2 Ab to reduce FBGC formation from peripheral blood monocytes in an in vitro assay. Our findings demonstrate a previously unreported involvement of CCL2 in FBGC formation, and suggest that FBGC are not the primary determinants of capsule formation in the FBR.

This article has been cited by other articles:

				D. M. Higgins, R. J. Basaraba, A. C. Hohnbaum, E. J. Lee, D. W. Grainger, and M. Gonzalez-Juarrero Localized Immunosuppressive Environment in the Foreign Body Response to Implanted Biomaterials Am. J. Pathol., July 1, 2009; 175(1): 161 - 170. [Abstract] [Full Text] [PDF]

				S. MacLauchlan, E. A. Skokos, N. Meznarich, D. H. Zhu, S. Raoof, J. M. Shipley, R. M. Senior, P. Bornstein, and T. R. Kyriakides Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9 J. Leukoc. Biol., April 1, 2009; 85(4): 617 - 626. [Abstract] [Full Text] [PDF]

				L. Helming, E. Tomasello, T. R. Kyriakides, F. O. Martinez, T. Takai, S. Gordon, and E. Vivier Essential Role of DAP12 Signaling in Macrophage Programming into a Fusion-Competent State Sci. Signal., October 28, 2008; 1(43): ra11 - ra11. [Abstract] [Full Text] [PDF]

				J. L. Moreno, I. Mikhailenko, M. M. Tondravi, and A. D. Keegan IL-4 promotes the formation of multinucleated giant cells from macrophage precursors by a STAT6-dependent, homotypic mechanism: contribution of E-cadherin J. Leukoc. Biol., December 1, 2007; 82(6): 1542 - 1553. [Abstract] [Full Text] [PDF]

				L. S. Miller, E. M. Pietras, L. H. Uricchio, K. Hirano, S. Rao, H. Lin, R. M. O'Connell, Y. Iwakura, A. L. Cheung, G. Cheng, et al. Inflammasome-Mediated Production of IL-1beta Is Required for Neutrophil Recruitment against Staphylococcus aureus In Vivo J. Immunol., November 15, 2007; 179(10): 6933 - 6942. [Abstract] [Full Text] [PDF]

				S. M. Jay, E. Skokos, F. Laiwalla, M.-M. Krady, and T. R. Kyriakides Foreign Body Giant Cell Formation Is Preceded by Lamellipodia Formation and Can Be Attenuated by Inhibition of Rac1 Activation Am. J. Pathol., August 1, 2007; 171(2): 632 - 640. [Abstract] [Full Text] [PDF]

				I. Lemaire, S. Falzoni, N. Leduc, B. Zhang, P. Pellegatti, E. Adinolfi, P. Chiozzi, and F. Di Virgilio Involvement of the Purinergic P2X7 Receptor in the Formation of Multinucleated Giant Cells J. Immunol., November 15, 2006; 177(10): 7257 - 7265. [Abstract] [Full Text] [PDF]

				L. F. L. Coelho, G. M. de Freitas Almeida, F. J. D. Mennechet, A. Blangy, and G. Uze Interferon-{alpha} and -{beta} differentially regulate osteoclastogenesis: Role of differential induction of chemokine CXCL11 expression PNAS, August 16, 2005; 102(33): 11917 - 11922. [Abstract] [Full Text] [PDF]

				A. Vignery Macrophage fusion: the making of osteoclasts and giant cells J. Exp. Med., August 1, 2005; 202(3): 337 - 340. [Abstract] [Full Text] [PDF]

				M. Yagi, T. Miyamoto, Y. Sawatani, K. Iwamoto, N. Hosogane, N. Fujita, K. Morita, K. Ninomiya, T. Suzuki, K. Miyamoto, et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells J. Exp. Med., August 1, 2005; 202(3): 345 - 351. [Abstract] [Full Text] [PDF]