Abstract
Macrophages undergo fusion with other macrophages to form the hallmark multinucleated giant cells of chronic inflammation. However, neither the existence of distinct morphological types of giant cells, the signaling pathways that induce their formation, the molecular mechanism(s) of macrophage fusion, nor the significance of macrophage multinucleation at chronic inflammatory sites are well understood. Our efforts have been focused on these unknowns, particularly as they relate to the foreign body-type giant cells that form on implanted biomaterials and biomedical devices. We have pursued the discoveries of human macrophage fusion factors (interleukin-4, interleukin-13, α-tocopherol) with emphasis on foreign body giant cells, and identified adhesion receptors and signaling intermediates, as well as an adhesion protein substrate (vitronectin) that supports macrophage fusion. Studies on the molecular mechanism of macrophage fusion have revealed it to be a mannose receptor-mediated phagocytic process with participation of the endoplasmic reticulum. Further phenotypic and functional investigations will foster new perspectives on these remarkable multinucleated cells and their physiological significances in multiple inflammatory processes.
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References
Langhans T (1868) Über Riesenzellen mit wandständigen Kernen in Tuberkeln und die fibröse Form des Tuberkels. Arch Pathol Anat 42:382–404
Chambers TJ, Spector WG (1982) Inflammatory giant cells. Immunobiology 161:283–289
Anderson JM (2000) Multinucleated giant cells. Curr Opin Hematol 7:40–47
Anderson JM (1988) Inflammatory response to implants. ASAIO Trans 34:101–107
Zhao OH, Anderson JM, Hiltner A et al (1992) Theoretical analysis on cell size distribution and kinetics of foreign-body giant cell formation in vivo on polyurethane elastomers. J Biomed Mat Res 26:1019–1038
Murch AR, Grounds MD, Marshall CA et al (1982) Direct evidence that inflammatory multinucleate giant cells form by fusion. J Pathol 137:177–180
Sutton JS, Weiss L (1966) Transformation of monocytes in tissue culture into macrophages, epithelioid cells, and multinucleated giant cells. An electron microscope study. J Cell Biol 28:303–332
Henson PM, Henson JE, Fittschen C et al (1988) Phagocytic cells: Degranulation and secretion. In: Gallin JI, Snyderman R (eds) Inflammation: Basic principles and clinical correlates, edn, Raven, New York, NY
Vignery A, Niven-Fairchild T, Ingbar DH et al (1989) Polarized distribution of Na+,K+-ATPase in giant cells elicited in vivo and in vitro. J Histochem Cytochem 37:1265–1271
Brodbeck WG, Anderson JM (2009) Giant cell formation and function. Curr Opin Hematol 16:53–57
McNally AK, Anderson JM (1995) Interleukin-4 induces foreign body giant cells from human monocytes/macrophages. Differential lymphokine regulation of macrophage fusion leads to morphological variants of multinucleated giant cells. Am J Pathol 147:1487–1499
DeFife KM, Jenney CR, Colton E et al (1999) Cytoskeletal and adhesive structural polarizations accompany IL-13-induced human macrophage fusion. J Histochem Cytochem 47:65–74
McNally AK, Anderson JM (2003) Foreign body-type multinucleated giant cell formation is potently induced by alpha-tocopherol and prevented by the diacylglycerol kinase inhibitor R59022. Am J Pathol 163:1147–1156
Enelow RI, Sullivan GW, Carper HT et al (1992) Induction of multinucleated giant cell formation from in vitro culture of human monocytes with interleukin-3 and interferon-gamma: comparison with other stimulating factors. Am J Respir Cell Mol Biol 6:57–62
McInnes A, Rennick DM (1988) Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells. J Exp Med 167:598–611
Weinberg JB, Hobbs MM, Misukonis MA (1984) Recombinant human gamma-interferon induces human monocyte polykaryon formation. Proc Natl Acad Sci USA 81:4554–4557
Takashima T, Ohnishi K, Tsuyuguchi I et al (1993) Differential regulation of formation of multinucleated giant cells from concanavalin A-stimulated human blood monocytes by IFN-gamma and IL-4. J Immunol 150:3002–3010
Most J, Neumayer HP, Dierich MP (1990) Cytokine-induced generation of multinucleated giant cells in vitro requires interferon-gamma and expression of LFA-1. Eur J Immunol 20:1661–1667
Orentas RJ, Reinlib L, Hildreth JE (1992) Anti-class II MHC antibody induces multinucleated giant cell formation from peripheral blood monocytes. J Leukoc Biol 51:199–209
Elliott MJ, Gamble JR, Park LS et al (1991) Inhibition of human monocyte adhesion by interleukin-4. Blood 77:2739–2745
Anderson JM, Defife K, McNally A et al (1999) Monocyte, macrophage and foreign body giant cell interactions with molecularly engineered surfaces. J Mat Sci 10:579–588
DeFife KM, Jenney CR, McNally AK et al (1997) Interleukin-13 induces human monocyte/macrophage fusion and macrophage mannose receptor expression. J Immunol 158:3385–3390
Kao WJ, McNally AK, Hiltner A et al (1995) Role for interleukin-4 in foreign-body giant cell formation on a poly(etherurethane urea) in vivo. J Biomed Mat Res 29:1267–1275
Rodriguez A, Macewan SR, Meyerson H et al (2009) The foreign body reaction in T-cell-deficient mice. J Biomed Mat Res 90:106–113
Gessner A, Mohrs K, Mohrs M (2005) Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J Immunol 174:1063–1072
O‘Connor GM, Hart OM, Gardiner CM (2006) Putting the natural killer cell in its place. Immunology 117:1–10
Brodbeck WG, Shive MS, Colton E et al (2002) Interleukin-4 inhibits tumor necrosis factor-alpha-induced and spontaneous apoptosis of biomaterial-adherent macrophages. J Lab Clin Med 139:90–100
Schubert MA, Wiggins MJ, DeFife KM et al (1996) Vitamin E as an antioxidant for poly(etherurethane urea): in vivo studies. Student Research Award in the Doctoral Degree Candidate Category, Fifth World Biomaterials Congress (22nd Annual Meeting of the Society for Biomaterials), Toronto, Canada, May 29-June 2, 1996. J Biomed Mat Res 32:493–504
Azzi A, Stocker A (2000) Vitamin E: non-antioxidant roles. Progress Lipid Res 39:231–255
McNally AK, Jones JA, Macewan SR et al (2008) Vitronectin is a critical protein adhesion substrate for IL-4-induced foreign body giant cell formation. J Biomed Mat Res 86:535–543
McNally AK, Anderson JM (2002) Beta1 and beta2 integrins mediate adhesion during macrophage fusion and multinucleated foreign body giant cell formation. Am J Pathol 160:621–630
Teitelbaum SL (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170:427–435
McNally AK, Macewan SR, Anderson JM (2007) alpha subunit partners to beta1 and beta2 integrins during IL-4-induced foreign body giant cell formation. J Biomed Mat Res 82:568–574
Ruoslahti E (1996) RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 12:697–715
Ratnikov BI, Partridge AW, Ginsberg MH (2005) Integrin activation by talin. J Thromb Haemost 3:1783–1790
Duong LT, Rodan GA (2000) PYK2 is an adhesion kinase in macrophages, localized in podosomes and activated by beta(2)-integrin ligation. Cell Motil Cytoskeleton 47:174–188
MacEwan SR, McNally A, Anderson JM (2007) Focal adhesion kinase, proline-rich tyrosine kinase-2, thrombospondin, and fascin-1 expression in adherent macrophages and foreign body giant cells. Society for Biomaterials Annual Meeting, Chicago, IL, April 18–21,703
DeFife KM, Jenney CR, Colton E et al (1999) Disruption of filamentous actin inhibits human macrophage fusion. Faseb J 13:823–832
McNally AK, Anderson JM (2005) Multinucleated giant cell formation exhibits features of phagocytosis with participation of the endoplasmic reticulum. Exp Mol Pathol 79:126–135
Marx J (2006) Cell biology. Podosomes and invadopodia help mobile cells step lively. Science 312:1868–1869
Calle Y, Burns S, Thrasher AJ et al (2006) The leukocyte podosome. Eur J Cell Biol 85:151–157
Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13:555–562
McNally A (1994) Mechanisms of monocyte/macrophage adhesion and fusion on different surfaces. PhD Thesis, Case Western Reserve University, Cleveland, OH
Brodbeck WG, Colton E, Anderson JM (2003) Effects of adsorbed heat labile serum proteins and fibrinogen on adhesion and apoptosis of monocytes/macrophages on biomaterials. J Mat Sci 14:671–675
Brodbeck WG, Patel J, Voskerician G et al (2002) Biomaterial adherent macrophage apoptosis is increased by hydrophilic and anionic substrates in vivo. Proc Natl Acad Sci USA 99:10287–10292
Jones JA, Dadsetan M, Collier TO et al (2004) Macrophage behavior on surface-modified polyurethanes. J Biomat Sci 15:567–584
Shive MS, Brodbeck WG, Anderson JM (2002) Activation of caspase 3 during shear stress-induced neutrophil apoptosis on biomaterials. J Biomed Mat Res 62:163–168
Stein M, Keshav S, Harris N et al (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176:287–292
McNally AK, DeFife KM, Anderson JM (1996) Interleukin-4-induced macrophage fusion is prevented by inhibitors of mannose receptor activity. Am J Pathol 149:975–985
McNally AK, Macewan SR, Anderson JM (2008) Foreign body-type multinucleated giant cell formation requires protein kinase C beta, delta, and zeta. Exp Mol Pathol 84:37–45
Carnevale KA, Cathcart MK (2003) Protein kinase C beta is required for human monocyte chemotaxis to MCP-1. J Biol Chem 278:25317–25322
Larsen EC, DiGennaro JA, Saito N et al (2000) Differential requirement for classic and novel PKC isoforms in respiratory burst and phagocytosis in RAW 264.7 cells. J Immunol 165:2809–2817
Larsson C (2006) Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal 18:276–284
Liu Q, Ning W, Dantzer R et al (1998) Activation of protein kinase C-zeta and phosphatidylinositol 3′-kinase and promotion of macrophage differentiation by insulin-like growth factor-I. J Immunol 160:1393–1401
Harsh DM, Blackwood RA (2001) Phospholipase A(2)-mediated fusion of neutrophil-derived membranes is augmented by phosphatidic acid. Biochem Biophys Res Commun 282:480–486
Jones JA, McNally AK, Chang DT et al (2008) Matrix metalloproteinases and their inhibitors in the foreign body reaction on biomaterials. J Biomed Mat Res 84:158–166
Mantovani A, Sica A, Locati M (2007) New vistas on macrophage differentiation and activation. Eur J Immunol 37:14–16
Mantovani A, Sica A, Sozzani S et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686
Porcheray F, Viaud S, Rimaniol AC et al (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142:481–489
Taylor PR, Martinez-Pomares L, Stacey M et al (2005) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944
Goerdt S, Politz O, Schledzewski K et al (1999) Alternative versus classical activation of macrophages. Pathobiology 67:222–226
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35
Gratchev A, Kzhyshkowska J, Utikal J et al (2005) Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Scand J Immunol 61:10–17
Moestrup SK, Moller HJ (2004) CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 36:347–354
Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73:209–212
Zhao Q, Topham N, Anderson JM et al (1991) Foreign-body giant cells and polyurethane biostability: in vivo correlation of cell adhesion and surface cracking. J Biomed Mat Res 25:177–183
Malefyt RW (1999) Role of interleukin-10, interleukin-4, and interleukin-13 in resolving inflammatory responses. In: Gallin JL, Snyderman R (eds) Inflammation: Basic principles and clinical correlates, edn, Lippincott Williams & Wilkins, Philadelphia, PA
Kodelja V, Muller C, Tenorio S et al (1997) Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197:478–493
Brigelius-Flohe R, Traber MG (1999) Vitamin E: function and metabolism. Faseb J 13:1145–1155
Chan SS, Monteiro HP, Schindler F et al (2001) Alpha-tocopherol modulates tyrosine phosphorylation in human neutrophils by inhibition of protein kinase C activity and activation of tyrosine phosphatases. Free Rad Res 35:843–856
Koh JS, Lieberthal W, Heydrick S et al (1998) Lysophosphatidic acid is a major serum noncytokine survival factor for murine macrophages which acts via the phosphatidylinositol 3-kinase signaling pathway. J Clin Invest 102:716–727
Lee IK, Koya D, Ishi H et al (1999) d-Alpha-tocopherol prevents the hyperglycemia induced activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle cell by an increase of DAG kinase activity. Diabetes Res Clin Pract 45:183–190
Topham MK, Prescott SM (1999) Mammalian diacylglycerol kinases, a family of lipid kinases with signaling functions. J Biol Chem 274:11447–11450
Leask A, Holmes A, Abraham DJ (2002) Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep 4:136–142
Jones JA, Chang DT, Meyerson H et al (2007) Proteomic analysis and quantification of cytokines and chemokines from biomaterial surface-adherent macrophages and foreign body giant cells. J Biomed Mat Res 83:585–596
Chang DT, Colton E, Matsuda T et al (2009) Lymphocyte adhesion and interactions with biomaterial adherent macrophages and foreign body giant cells. J Biomed Mat Res 91:1210–1220
Kirk JT, McNally AK, Anderson JM (2010) Polymorphonuclear leukocyte inhibition of monocytes/macrophages in the foreign body reaction. J Biomed Mat Res 94:683–687
Moreno JL, Kaczmarek M, Keegan AD et al (2003) IL-4 suppresses osteoclast development and mature osteoclast function by a STAT6-dependent mechanism: irreversible inhibition of the differentiation program activated by RANKL. Blood 102:1078–1086
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McNally, A.K., Anderson, J.M. (2011). Macrophage Fusion and Multinucleated Giant Cells of Inflammation. In: Dittmar, T., Zänker, K.S. (eds) Cell Fusion in Health and Disease. Advances in Experimental Medicine and Biology, vol 713. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0763-4_7
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DOI: https://doi.org/10.1007/978-94-007-0763-4_7
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