Macrophage Fusion and Multinucleated Giant Cells of Inflammation

  • Amy K. McNally
  • James M. Anderson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 713)


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.


Giant Cell Connective Tissue Growth Factor Adhesion Structure Foreign Body Giant Cell Diacylglycerol Kinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Langhans T (1868) Über Riesenzellen mit wandständigen Kernen in Tuberkeln und die fibröse Form des Tuberkels. Arch Pathol Anat 42:382–404CrossRefGoogle Scholar
  2. 2.
    Chambers TJ, Spector WG (1982) Inflammatory giant cells. Immunobiology 161:283–289PubMedGoogle Scholar
  3. 3.
    Anderson JM (2000) Multinucleated giant cells. Curr Opin Hematol 7:40–47PubMedCrossRefGoogle Scholar
  4. 4.
    Anderson JM (1988) Inflammatory response to implants. ASAIO Trans 34:101–107PubMedCrossRefGoogle Scholar
  5. 5.
    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 26:1019–1038CrossRefGoogle Scholar
  6. 6.
    Murch AR, Grounds MD, Marshall CA et al (1982) Direct evidence that inflammatory multinucleate giant cells form by fusion. J Pathol 137:177–180PubMedCrossRefGoogle Scholar
  7. 7.
    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 28:303–332PubMedCrossRefGoogle Scholar
  8. 8.
    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, NYGoogle Scholar
  9. 9.
    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 37:1265–1271PubMedCrossRefGoogle Scholar
  10. 10.
    Brodbeck WG, Anderson JM (2009) Giant cell formation and function. Curr Opin Hematol 16:53–57PubMedCrossRefGoogle Scholar
  11. 11.
    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 147:1487–1499PubMedGoogle Scholar
  12. 12.
    DeFife KM, Jenney CR, Colton E et al (1999) Cytoskeletal and adhesive structural polarizations accompany IL-13-induced human macrophage fusion. J Histochem Cytochem 47:65–74PubMedCrossRefGoogle Scholar
  13. 13.
    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 163:1147–1156PubMedCrossRefGoogle Scholar
  14. 14.
    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 6:57–62PubMedGoogle Scholar
  15. 15.
    McInnes A, Rennick DM (1988) Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells. J Exp Med 167:598–611PubMedCrossRefGoogle Scholar
  16. 16.
    Weinberg JB, Hobbs MM, Misukonis MA (1984) Recombinant human gamma-interferon induces human monocyte polykaryon formation. Proc Natl Acad Sci USA 81:4554–4557PubMedCrossRefGoogle Scholar
  17. 17.
    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 150:3002–3010PubMedGoogle Scholar
  18. 18.
    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 20:1661–1667PubMedCrossRefGoogle Scholar
  19. 19.
    Orentas RJ, Reinlib L, Hildreth JE (1992) Anti-class II MHC antibody induces multinucleated giant cell formation from peripheral blood monocytes. J Leukoc Biol 51:199–209PubMedGoogle Scholar
  20. 20.
    Elliott MJ, Gamble JR, Park LS et al (1991) Inhibition of human monocyte adhesion by interleukin-4. Blood 77:2739–2745PubMedGoogle Scholar
  21. 21.
    Anderson JM, Defife K, McNally A et al (1999) Monocyte, macrophage and foreign body giant cell interactions with molecularly engineered surfaces. J Mat Sci 10:579–588Google Scholar
  22. 22.
    DeFife KM, Jenney CR, McNally AK et al (1997) Interleukin-13 induces human monocyte/macrophage fusion and macrophage mannose receptor expression. J Immunol 158:3385–3390PubMedGoogle Scholar
  23. 23.
    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 29:1267–1275CrossRefGoogle Scholar
  24. 24.
    Rodriguez A, Macewan SR, Meyerson H et al (2009) The foreign body reaction in T-cell-deficient mice. J Biomed Mat Res 90:106–113CrossRefGoogle Scholar
  25. 25.
    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 174:1063–1072PubMedGoogle Scholar
  26. 26.
    O‘Connor GM, Hart OM, Gardiner CM (2006) Putting the natural killer cell in its place. Immunology 117:1–10PubMedCrossRefGoogle Scholar
  27. 27.
    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 139:90–100PubMedCrossRefGoogle Scholar
  28. 28.
    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 32:493–504Google Scholar
  29. 29.
    Azzi A, Stocker A (2000) Vitamin E: non-antioxidant roles. Progress Lipid Res 39:231–255CrossRefGoogle Scholar
  30. 30.
    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 86:535–543CrossRefGoogle Scholar
  31. 31.
    McNally AK, Anderson JM (2002) Beta1 and beta2 integrins mediate adhesion during macrophage fusion and multinucleated foreign body giant cell formation. Am J Pathol 160:621–630PubMedCrossRefGoogle Scholar
  32. 32.
    Teitelbaum SL (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170:427–435PubMedCrossRefGoogle Scholar
  33. 33.
    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 82:568–574CrossRefGoogle Scholar
  34. 34.
    Ruoslahti E (1996) RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 12:697–715PubMedCrossRefGoogle Scholar
  35. 35.
    Ratnikov BI, Partridge AW, Ginsberg MH (2005) Integrin activation by talin. J Thromb Haemost 3:1783–1790PubMedCrossRefGoogle Scholar
  36. 36.
    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 47:174–188PubMedCrossRefGoogle Scholar
  37. 37.
    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 18–21,703Google Scholar
  38. 38.
    DeFife KM, Jenney CR, Colton E et al (1999) Disruption of filamentous actin inhibits human macrophage fusion. Faseb J 13:823–832PubMedGoogle Scholar
  39. 39.
    McNally AK, Anderson JM (2005) Multinucleated giant cell formation exhibits features of phagocytosis with participation of the endoplasmic reticulum. Exp Mol Pathol 79:126–135PubMedCrossRefGoogle Scholar
  40. 40.
    Marx J (2006) Cell biology. Podosomes and invadopodia help mobile cells step lively. Science 312:1868–1869PubMedCrossRefGoogle Scholar
  41. 41.
    Calle Y, Burns S, Thrasher AJ et al (2006) The leukocyte podosome. Eur J Cell Biol 85:151–157PubMedCrossRefGoogle Scholar
  42. 42.
    Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13:555–562PubMedCrossRefGoogle Scholar
  43. 43.
    McNally A (1994) Mechanisms of monocyte/macrophage adhesion and fusion on different surfaces. PhD Thesis, Case Western Reserve University, Cleveland, OHGoogle Scholar
  44. 44.
    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 14:671–675Google Scholar
  45. 45.
    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 99:10287–10292PubMedCrossRefGoogle Scholar
  46. 46.
    Jones JA, Dadsetan M, Collier TO et al (2004) Macrophage behavior on surface-modified polyurethanes. J Biomat Sci 15:567–584CrossRefGoogle Scholar
  47. 47.
    Shive MS, Brodbeck WG, Anderson JM (2002) Activation of caspase 3 during shear stress-induced neutrophil apoptosis on biomaterials. J Biomed Mat Res 62:163–168CrossRefGoogle Scholar
  48. 48.
    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 176:287–292PubMedCrossRefGoogle Scholar
  49. 49.
    McNally AK, DeFife KM, Anderson JM (1996) Interleukin-4-induced macrophage fusion is prevented by inhibitors of mannose receptor activity. Am J Pathol 149:975–985PubMedGoogle Scholar
  50. 50.
    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 84:37–45PubMedCrossRefGoogle Scholar
  51. 51.
    Carnevale KA, Cathcart MK (2003) Protein kinase C beta is required for human monocyte chemotaxis to MCP-1. J Biol Chem 278:25317–25322PubMedCrossRefGoogle Scholar
  52. 52.
    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 165:2809–2817PubMedGoogle Scholar
  53. 53.
    Larsson C (2006) Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal 18:276–284PubMedCrossRefGoogle Scholar
  54. 54.
    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 160:1393–1401PubMedGoogle Scholar
  55. 55.
    Harsh DM, Blackwood RA (2001) Phospholipase A(2)-mediated fusion of neutrophil-derived membranes is augmented by phosphatidic acid. Biochem Biophys Res Commun 282:480–486PubMedCrossRefGoogle Scholar
  56. 56.
    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 84:158–166CrossRefGoogle Scholar
  57. 57.
    Mantovani A, Sica A, Locati M (2007) New vistas on macrophage differentiation and activation. Eur J Immunol 37:14–16PubMedCrossRefGoogle Scholar
  58. 58.
    Mantovani A, Sica A, Sozzani S et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686PubMedCrossRefGoogle Scholar
  59. 59.
    Porcheray F, Viaud S, Rimaniol AC et al (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142:481–489PubMedGoogle Scholar
  60. 60.
    Taylor PR, Martinez-Pomares L, Stacey M et al (2005) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944PubMedCrossRefGoogle Scholar
  61. 61.
    Goerdt S, Politz O, Schledzewski K et al (1999) Alternative versus classical activation of macrophages. Pathobiology 67:222–226PubMedCrossRefGoogle Scholar
  62. 62.
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedCrossRefGoogle Scholar
  63. 63.
    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 61:10–17PubMedCrossRefGoogle Scholar
  64. 64.
    Moestrup SK, Moller HJ (2004) CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 36:347–354PubMedCrossRefGoogle Scholar
  65. 65.
    Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73:209–212PubMedCrossRefGoogle Scholar
  66. 66.
    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 25:177–183CrossRefGoogle Scholar
  67. 67.
    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, PAGoogle Scholar
  68. 68.
    Kodelja V, Muller C, Tenorio S et al (1997) Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197:478–493PubMedGoogle Scholar
  69. 69.
    Brigelius-Flohe R, Traber MG (1999) Vitamin E: function and metabolism. Faseb J 13:1145–1155PubMedGoogle Scholar
  70. 70.
    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 35:843–856CrossRefGoogle Scholar
  71. 71.
    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 102:716–727PubMedCrossRefGoogle Scholar
  72. 72.
    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 45:183–190PubMedCrossRefGoogle Scholar
  73. 73.
    Topham MK, Prescott SM (1999) Mammalian diacylglycerol kinases, a family of lipid kinases with signaling functions. J Biol Chem 274:11447–11450PubMedCrossRefGoogle Scholar
  74. 74.
    Leask A, Holmes A, Abraham DJ (2002) Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep 4:136–142PubMedCrossRefGoogle Scholar
  75. 75.
    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 83:585–596CrossRefGoogle Scholar
  76. 76.
    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 91:1210–1220CrossRefGoogle Scholar
  77. 77.
    Kirk JT, McNally AK, Anderson JM (2010) Polymorphonuclear leukocyte inhibition of monocytes/macrophages in the foreign body reaction. J Biomed Mat Res 94:683–687Google Scholar
  78. 78.
    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 102:1078–1086PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of Pathology, Wolstein Research BuildingCase Western Reserve UniversityClevelandUSA

Personalised recommendations