Chapter 20 : The Functional Heterogeneity of Activated Macrophages

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

The Functional Heterogeneity of Activated Macrophages, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap20-1.gif /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap20-2.gif


New and improved ways to phenotype cells in tissue have led to a better understanding of the heterogeneity of activated macrophages. Macrophages are derived from progenitor cells in the bone marrow. Once in tissue, macrophages can undergo profound physiological changes in response to the combination of cytokines and inflammatory stimuli they encounter there. Apoptotic cells are efficiently eliminated by macrophages through phagocytosis. This process can result in the production of transforming growth factor-β (TGF-β) by macrophages, a cytokine that is well known as a strong suppressor of T-cell activation and antibody secretion by B cells. Adenosine is a purine nucleoside that can accumulate in the extracellular space following stress or inflammation. Macrophages have four adenosine receptors, A1, A2A, A2B, and A3, all of which are seven-transmembrane, G-protein- coupled receptors (GPCRs). Macrophage-stimulating protein (MSP), also known as hepatocyte growth factor-like (HGFL), is a plasma protein belonging to the plasminogen-related growth factor (PRGF) family. Treatment of macrophages with glucocorticoids (GCs) has a profound inhibitory effect on the production of proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-12 (IL-12). This inhibition can skew immune responses toward a Th2 response and prevent macrophage-mediated inflammation. The Toll-like receptor (TLR) pathway represents an activating avenue that has the potential to lead to new adjuvants and better vaccines. Conversely, the uncovering of the signaling pathway leading to IL-10 overproduction has the potential to lead to a novel class of anti-inflammatory compounds that induce IL-10 production from macrophages.

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

IL-10 cytokine production from macrophages following differential priming and stimulation. Macrophages were primed overnight with either 100 U/ml IFN-γ (black bars) or 10 U/ml IL-4 (gray bars). The next morning, cells were stimulated with either 10 ng/ml of lipopolysaccharide alone (LPS) or LPS plus immune complexes consisting of OVA:anti-OVA (LPS+IC). Some cells received no stimulation (NS). After 18 h, IL-10 in supernatants was measured by ELISA. No detectable IL-10 was found in unstimulated cells regardless of the priming. Macrophages primed with IL-4 made more IL-10 in response to LPS than did classically activated (IFN-γ-primed) macrophages. Cells stimulated with LPS in the presence of IC made substantially more IL-10, regardless of how they were primed.

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

T-cell proliferation in response to antigen presented by different populations of macrophages. Macrophages were primed overnight with IL-4 (top two panels) or IFN-γ (bottom panel). The following morning, 150 μg/ml OVA was added to each population. Macrophages in the top panel received OVA alone. Macrophages in the middle and bottom panels received OVA along with 10 ng/ml LPS. After 96 h of coculture with carboxyfluorescein diacetate, the proliferation of succinimidyl ester (CFSE)-labeled CD4 T cells from DO11.10 mice was measured by the dilution of CFSE. IL-4-primed macrophages (top panel) support only modest T-cell proliferation, and the addition of LPS to stimulate IL-4-primed macrophages (middle panel) does not enhance their ability to present antigen. Mφ-II (bottom panel) readily induce T-cell proliferation as evidenced by the high degree of CFSE dilution.

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Antibody production in DO11.10 mice after immunization with OVA along with different macrophage populations. Macrophages from BALB/c mice were activated in vitro with LPS alone (Type 1 Mφ) or LPS plus an irrelevant immune complex, E-IgG (Type 2 Mφ). One hour after activation, 2 × 10 Mφ were injected intraperitoneally into mice along with 50 μg of OVA in the absence of adjuvant. This procedure was repeated 10 days later. Nine days after the second immunization, mice were bled, and OVA-specific antibody (Ig) (black bars), IgG1 (open bars), and IgG2a (dark gray bars) were measured by ELISA (* < 0.05; ** < 0.01).

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Aggarwal, B. B. 2003. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3: 745756.
2. Akashi, K.,, D. Traver,, T. Miyamoto, and, I. L. Weissman. 2000. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404: 193197.
3. Anderson, C. F.,, J. S. Gerber, and, D. M. Mosser. 2002. Modulating macrophage function with IgG immune complexes. J. Endotoxin. Res. 8: 477481.
4. Anderson, C. F.,, and D. M. Mosser. 2002a. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J. Leukoc. Biol. 72: 101106.
5. Anderson, C. F.,, and D. M. Mosser. 2002b. Cutting edge: biasing immune responses by directing antigen to macrophage Fc gamma receptors. J. Immunol. 168: 36973701.
6. Auffray, C.,, D. Fogg,, M. Garfa,, G. Elain,, O. Join-Lambert,, S. Kayal,, S. Sarnacki,, A. Cumano,, G. Lauvau, and, F. Geissmann. 2007. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317: 666670.
7. Barker, R. N.,, L. Erwig,, W. P. Pearce,, A. Devine, and, A. J. Rees. 1999. Differential effects of necrotic or apoptotic cell uptake on antigen presentation by macrophages. Pathobiology 67: 302305.
8. Baumgart, D. C.,, and S. R. Carding. 2007. Inflammatory bowel disease: cause and immunobiology. Lancet 369: 16271640.
9. Baumgart, D. C.,, and W. J. Sandborn. 2007. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 369: 16411657.
10. Biswas, S. K.,, L. Gangi,, S. Paul,, T. Schioppa,, A. Saccani,, M. Sironi,, B. Bottazzi,, A. Doni,, B. Vincenzo,, F. Pasqualini,, L. Vago,, M. Nebuloni,, A. Mantovani, and, A. Sica. 2006. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107: 21122122.
11. Boven, L. A.,, M. van Meurs,, R. G. Boot,, A. Mehta,, L. Boon,, J. M. Aerts, and, J. D. Laman. 2004. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Am. J. Clin. Pathol. 122: 359369.
12. Brown, S. B.,, and J. Savill. 1999. Phagocytosis triggers macrophage release of Fas ligand and induces apoptosis of bystander leukocytes. J. Immunol. 162: 480485.
13. Byrne, A.,, and D. J. Reen. 2002. Lipopolysaccharide induces rapid production of IL-10 by monocytes in the presence of apoptotic neutrophils. J. Immunol. 168: 19681977.
14. Chen, Y. Q.,, J. H. Fisher, and, M. H. Wang. 1998. Activation of the RON receptor tyrosine kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine peritoneal exudate macrophages: phosphatidylinositol-3 kinase is required for RON-mediated inhibition of iNOS expression. J. Immunol. 161: 49504959.
15. Chung, E. Y.,, J. Liu,, Y. Homma,, Y. Zhang,, A. Brendolan,, M. Saggese,, J. Han,, R. Silverstein,, L. Selleri, and, X. Ma. 2007. Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homodomain proteins Pbx1 and Prep-1. Immunity 27: 952964.
16. Cohn, Z. A. 1978. Activation of mononuclear phagocytes: fact, fancy, and future. J. Immunol. 121: 813816.
17. Correll, P. H.,, A. Iwama,, S. Tondat,, G. Mayrhofer,, T. Suda, and, A. Bernstein. 1997. Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase. Genes Funct. 1: 6983.
18. Csoka, B.,, Z. H. Nemeth,, L. Virag,, P. Gergely,, S. J. Leibovich,, P. Pacher,, C. X. Sun,, M. R. Blackburn,, E. S. Vizi,, E. A. Deitch, and, G. Hasko. 2007. A2A adenosine receptors and C/EBP[beta] are crucially required for IL-10 production by macrophages exposed to E. coli. Blood 110: 26852695.
19. D’Andrea, A.,, X. Ma,, M. Aste-Amezaga,, C. Paganin, and, G. Trinchieri. 1995. Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production. J. Exp. Med. 181: 537546.
20. Danilkovitch, A.,, A. Skeel, and, E. J. Leonard. 1999. Macrophage stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism. Exp. Cell Res. 248: 575582.
21. Desnues, B.,, H. Lepidi,, D. Raoult, and, J. L. Mege. 2005. Whipple disease: intestinal infiltrating cells exhibit a transcriptional pattern of M2/alternatively activated macrophages. J. Infect. Dis. 192: 16421646.
22. de Visser, K. E.,, A. Eichten, and, L. M. Coussens. 2006. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 6: 2437.
23. de Visser, K. E.,, L. V. Korets, and, L. M. Coussens. 2005. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell. 7: 411423.
24. Ebert, E. C.,, V. Mehta, and, K. M. Das. 2005. Activation antigens on colonic T cells in inflammatory bowel disease: effects of IL-10. Clin. Exp. Immunol. 140: 157165.
25. Edwards, J. P.,, X. Zhang,, K. A. Frauwirth, and, D. M. Mosser. 2006. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 80: 12981307.
26. Fadok, V. A.,, D. L. Bratton,, A. Konowal,, P. W. Freed,, J. Y. Westcott, and, P. M. Henson. 1998. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J. Clin. Investig. 101: 890898.
27. Fadok, V. A.,, D. L. Bratton,, D. M. Rose,, A. Pearson,, R. A. Ezekewitz, and, P. M. Henson. 2000. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405: 8590.
28. Fogg, D. K.,, C. Sibon,, C. Miled,, S. Jung,, P. Aucouturier,, D. R. Littman,, A. Cumano, and, F. Geissmann. 2006. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311: 8387.
29. Garn, H.,, A. Siese,, S. Stumpf,, P. J. Barth,, B. Muller, and, D. Gemsa. 2003. Shift toward an alternatively activated macrophage response in lungs of NO2-exposed rats. Am. J. Respir. Cell Mol. Biol. 28: 386396.
30. Gaudino, G.,, A. Follenzi,, L. Naldini,, C. Collesi,, M. Santoro,, K. A. Gallo,, P. J. Godowski, and, P. M. Comoglio. 1994. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J. 13: 35243532.
31. Geissmann, F.,, S. Jung, and, D. R. Littman. 2003. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 7182.
32. Gerber, J. S.,, and D. M. Mosser. 2001. Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors. J. Immunol. 166: 68616868.
33. Goerdt, S.,, and C. E. Orfanos. 1999. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10: 137142.
34. Gordon, S. 2003. Alternative activation of macrophages. Nat. Rev. Immunol. 3: 2335.
35. Gordon, S.,, and P. R. Taylor. 2005. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5: 953964.
36. Granger, S. W.,, and S. Rickert. 2003. LIGHT-HVEM signaling and the regulation of T cell-mediated immunity. Cytokine Growth Factor Rev. 14: 289296.
37. Gray, M. J.,, M. Poljakovic,, D. Kepka-Lenhart, and, S. M. Morris, Jr. 2005. Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta. Gene 353: 98106.
38. Greenwald, R. J.,, G. J. Freeman, and, A. H. Sharpe. 2005. The B7 family revisited. Annu. Rev. Immunol. 23: 515548.
39. Gu, J.,, and C. Korteweg. 2007. Pathology and pathogenesis of severe acute respiratory syndrome. Am. J. Pathol. 170: 11361147.
40. Harding, C. V.,, L. Ramachandra, and, M. J. Wick. 2003. Interaction of bacteria with antigen presenting cells: influences on antigen presentation and antibacterial immunity. Curr. Opin. Immunol. 15: 112119.
41. Hasko, G.,, D. G. Kuhel,, J. F. Chen,, M. A. Schwarzschild,, E. A. Deitch,, J. G. Mabley,, A. Marton, and, C. Szabo. 2000a. Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J. 14: 20652074.
42. Hasko, G.,, D. G. Kuhel,, Z. H. Nemeth,, J. G. Mabley,, R. F. Stachlewitz,, L. Virag,, Z. Lohinai,, G. J. Southan,, A. L. Salzman, and, C. Szabo. 2000b. Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J. Immunol. 164: 10131019.
43. Henson, P. 2003. Suppression of macrophage inflammatory responses by PPARs. Proc. Natl. Acad. Sci. USA 100: 62956296.
44. Henson, P. M.,, D. L. Bratton, and, V. A. Fadok. 2001. The phosphatidylserine receptor: a crucial molecular switch? Nat. Rev. Mol. Cell Biol. 2: 627633.
45. Hesse, M.,, M. Modolell,, A. C. La Flamme,, M. Schito,, J. M. Fuentes,, A. W. Cheever,, E. J. Pearce, and, T. A. Wynn. 2001. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167: 65336544.
46. Hotchkiss, R. S.,, K. C. Chang,, M. H. Grayson,, K. W. Tinsley,, B. S. Dunne,, C. G. Davis,, D. F. Osborne, and, I. E. Karl. 2003. Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proc. Natl. Acad. Sci. USA 100: 67246729.
47. Hume, D. A. 2006. The mononuclear phagocyte system. Curr. Opin. Immunol. 18: 4953.
48. Huynh, M. L.,, V. A. Fadok, and, P. M. Henson. 2002. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J. Clin. Investig. 109: 4150.
49. Iwakura, Y.,, and H. Ishigame. 2006. The IL-23/IL-17 axis in inflammation. J. Clin. Investig. 116: 12181222.
50. Johann, A. M.,, V. Barra,, A. M. Kuhn,, A. Weigert,, A. von Knethen, and, B. Brune. 2007. Apoptotic cells induce arginase II in macrophages, thereby attenuating NO production. FASEB J. 21: 27042712.
51. Kambayashi, T.,, C. O. Jacob, and, G. Strassmann. 1996. IL-4 and IL-13 modulate IL-10 release in endotoxin-stimulated murine peritoneal mononuclear phagocytes. Cell Immunol. 171: 153158.
52. Karp, C. L.,, S. H. el-Safi,, T. A. Wynn,, M. M. Satti,, A. M. Kordofani,, F. A. Hashim,, M. Hag-Ali,, F. A. Neva,, T. B. Nutman, and, D. L. Sacks. 1993. In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma. J. Clin. Investig. 91: 16441648.
53. Kash, J. C.,, C. F. Basler,, A. Garcia-Sastre,, V. Carter,, R. Billharz,, D. E. Swayne,, R. M. Przygodzki,, J. K. Taubenberger,, M. G. Katze, and, T. M. Tumpey. 2004. Global host immune response: pathogenesis and transcriptional profiling of type A influenza viruses expressing the hemagglutinin and neuraminidase genes from the 1918 pandemic virus. J. Virol. 78: 94999511.
54. Kim, S.,, K. B. Elkon, and, X. Ma. 2004. Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity 21: 643653.
55. Kryczek, I.,, L. Zou,, P. Rodriguez,, G. Zhu,, S. Wei,, P. Mottram,, M. Brumlik,, P. Cheng,, T. Curiel,, L. Myers,, A. Lack-ner,, X. Alvarez,, A. Ochoa,, L. Chen, and, W. Zou. 2006. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203: 871881.
56. Kumar, S.,, and R. Jack. 2006. Origin of monocytes and their differentiation to macrophages and dendritic cells. J. Endotoxin. Res. 12: 278284.
57. Kzhyshkowska, J.,, S. Mamidi,, A. Gratchev,, E. Kremmer,, C. Schmuttermaier,, L. Krusell,, G. Haus,, J. Utikal,, K. Schledzewski,, J. Scholtze, and, S. Goerdt. 2006a. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 107: 32213228.
58. Kzhyshkowska, J.,, G. Workman,, M. Cardo-Vila,, W. Arap,, R. Pasqualini,, A. Gratchev,, L. Krusell,, S. Goerdt, and, E. H. Sage. 2006b. Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J. Immunol. 176: 58255832.
59. Landsman, L.,, C. Varol, and, S. Jung. 2007. Distinct differentiation potential of blood monocyte subsets in the lung. J. Immunol. 178: 20002007.
60. Langrish, C. L.,, Y. Chen,, W. M. Blumenschein,, J. Mattson,, B. Basham,, J. D. Sedgwick,, T. McClanahan,, R. A. Kastelein, and, D. J. Cua. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201: 233240.
61. Le Moine, O.,, P. Stordeur,, L. Schandené,, A. Marchant,, D. de Groote,, M. Goldman, and, J. Devière. 1996. Adenosine enhances IL-10 secretion by human monocytes. J. Immunol. 156: 44084414.
62. Leon, B.,, M. Lopez-Bravo, and, C. Ardavin. 2007. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26: 519531.
63. Leonard, E. J.,, and A. H. Skeel. 1978. Isolation of macrophage stimulating protein (MSP) from human serum. Exp. Cell Res. 114: 117126.
64. Levy, D. E.,, and J. E. Darnell, Jr. 2002. Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3: 651662.
65. Lin, E. Y.,, and J. W. Pollard. 2007. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 67: 50645066.
66. Liu, J.,, S. Cao,, L. M. Herman, and, X. Ma. 2003. Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1. J. Exp. Med. 198: 12651276.
67. Liu, J.,, X. Guan, and, X. Ma. 2007. Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-gamma-mediated pathways. J. Exp. Med. 204: 141152.
68. Liu, Q. P.,, K. Fruit,, J. Ward, and, P. H. Correll. 1999. Negative regulation of macrophage activation in response to IFN-gamma and lipopolysaccharide by the STK/RON receptor tyrosine kinase. J. Immunol. 163: 66066613.
69. Liu, T.,, S. M. Dhanasekaran,, H. Jin,, B. Hu,, S. A. Tomlins,, A. M. Chinnaiyan, and, S. H. Phan. 2004. FIZZ1 stimulation of myofibroblast differentiation. Am. J. Pathol. 164: 13151326.
70. Loke, P.,, A. S. MacDonald,, A. Robb,, R. M. Maizels, and, J. E. Allen. 2000. Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact. Eur. J. Immunol. 30: 26692678.
71. Lucas, M.,, L. M. Stuart,, J. Savill, and, A. Lacy-Hulbert. 2003. Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion. J. Immunol. 171: 26102615.
72. Lucas, M.,, X. Zhang,, V. Prasanna, and, D. M. Mosser. 2005. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175: 469477.
73. MacMicking, J.,, Q. W. Xie, and, C. Nathan. 1997. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15: 323350.
74. Maizels, R. M.,, A. Balic,, N. Gomez-Escobar,, M. Nair,, M. D. Taylor, and, J. E. Allen. 2004. Helminth parasites—masters of regulation. Immunol. Rev. 201: 89116.
75. Mantovani, A.,, T. Schioppa,, C. Porta,, P. Allavena, and, A. Sica. 2006. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 25: 315322.
76. Mantovani, A.,, A. Sica, and, M. Locati. 2007. New vistas on macrophage differentiation and activation. Eur. J. Immunol. 37: 1416.
77. Mantovani, A.,, S. Sozzani,, M. Locati,, P. Allavena, and, A. Sica. 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23: 549555.
78. Marathe, C.,, M. N. Bradley,, C. Hong,, F. Lopez,, C. M. Ruiz de Galarreta,, P. Tontonoz, and, A. Castrillo. 2006. The arginase II gene is an anti-inflammatory target of liver X receptor in macrophages. J. Biol. Chem. 281: 3219732206.
79. Martinez, F. O.,, S. Gordon,, M. Locati, and, A. Mantovani. 2006. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177: 73037311.
80. Mauri, D. N.,, R. Ebner,, R. I. Montgomery,, K. D. Kochel,, T. C. Cheung,, G. L. Yu,, S. Ruben,, M. Murphy,, R. J. Eisenberg,, G. H. Cohen,, P. G. Spear, and, C. F. Ware. 1998. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8: 2130.
81. Menendez-Benito, V.,, and J. Neefjes. 2007. Autophagy in MHC class II presentation: sampling from within. Immunity 26: 13.
82. Miles, S. A.,, S. M. Conrad,, R. G. Alves,, S. M. Jeronimo, and, D. M. Mosser. 2005. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J. Exp. Med. 201: 747754.
83. Mills, C. D. 2001. Macrophage arginine metabolism to ornithine/urea or nitric oxide/citrulline: a life or death issue. Crit. Rev. Immunol. 21: 399425.
84. Mills, C. D.,, K. Kincaid,, J. M. Alt,, M. J. Heilman, and, A. M. Hill. 2000. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164: 61666173.
85. Morrison, A. C.,, and P. H. Correll. 2002. Activation of the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase by macrophage-stimulating protein results in the induction of arginase activity in murine peritoneal macrophages. J. Immunol. 168: 853860.
86. Morrison, A. C.,, C. B. Wilson,, M. Ray, and, P. H. Correll. 2004. Macrophage-stimulating protein, the ligand for the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase, inhibits IL-12 production by primary peritoneal macrophages stimulated with IFN-gamma and lipopolysaccharide. J. Immunol. 172: 18251832.
87. Mosser, D. M. 2003. The many faces of macrophage activation. J. Leukoc. Biol. 73: 209212.
88. Muroaka, R. S.,, W. Y. Sun,, M. C. Colbert,, S. E. Waltze,, D. P. Witte,, J. L. Degen, and, S. J. Friezner-Degen. 1999. The Ron/STK receptor tyrosine kinase is essential for periimplantation development in the mouse. J. Clin. Invest. 103: 12771285.
89. Nair, M. G.,, K. J. Guild, and, D. Artis. 2006. Novel effector molecules in type 2 inflammation: lessons drawn from helminth infection and allergy. J. Immunol. 177: 13931399.
90. Najar, H. M.,, S. Ruhl,, A. C. Bru-Capdeville, and, J. H. Peters. 1990. Adenosine and its derivatives control human monocyte differentiation into highly accessory cells versus macrophages. J. Leukoc. Biol. 47: 429439.
91. Namangala, B.,, B. P. De,, W. Noel,, L. Brys, and, A. Beschin. 2001. Alternative versus classical macrophage activation during experimental African trypanosomosis. J. Leukoc. Biol. 69: 387396.
92. Nemeth, Z. H.,, C. S. Lutz,, B. Csoka,, E. A. Deitch,, S. J. Leibovich,, W. C. Gause,, M. Tone,, P. Pacher,, E. S. Vizi, and, G. Hasko. 2005. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J. Immunol. 175: 82608270.
93. Nys, M.,, R. Laub,, P. Damas,, D. Sondag,, T. Goethals,, D. Jamaer,, L. Joassin, and, M. Lamy. 1996. Screening and characterization of specific anti-lipopolysaccharide antibodies in Belgian blood donors by enzyme-linked immunosorbent assays. Eur. J. Clin. Invest. 26: 11341142.
94. Orkin, S. H. 2000. Diversification of haematopoietic stem cells to specific lineages. Nat. Rev. Genet. 1: 5764.
95. Oskouian, B.,, and J. Saba. 2007. Sphingosine-1-phosphate metabolism and intestinal tumorigenesis: lipid signaling strikes again. Cell Cycle 6: 522527.
96. Palese, P. 2004. Influenza: old and new threats. Nat. Med. 10: S82S87.
97. Panther, E.,, S. Corinti,, M. Idzko,, Y. Herouy,, M. Napp,, A. la Sala,, G. Girolomoni, and, J. Norgauer. 2003. Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101: 39853990.
98. Pauleau, A. L.,, R. Rutschman,, R. Lang,, A. Pernis,, S. S. Watowich, and, P. J. Murray. 2004. Enhancer-mediated control of macrophage-specific arginase I expression. J. Immunol. 172: 75657573.
99. Penengo, L.,, C. Rubin,, Y. Yarden, and, G. Gaudino. 2003. c-Cbl is a critical modulator of the Ron tyrosine kinase receptor. Oncogene 22: 36693679.
100. Perlman, S.,, and A. A. Dandekar. 2005. Immunopathogenesis of coronavirus infections: implications for SARS. Nat. Rev. Immunol. 5: 917927.
101. Pflanz, S.,, J. C. Timans,, J. Cheung,, R. Rosales,, H. Kanzler,, J. Gilbert,, L. Hibbert,, T. Churakova,, M. Travis,, E. Vaisberg,, W. M. Blumenschein,, J. D. Mattson,, J. L. Wagner,, W. To,, S. Zurawski,, T. K. McClanahan,, D. M. Gorman,, J. F. Bazan,, M. R. de Waal,, D. Rennick, and, R. A. Kastelein. 2002. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 16: 779790.
102. Rauh, M. J.,, V. Ho,, C. Pereira,, A. Sham,, L. M. Sly,, V. Lam,, L. Huxham,, A. I. Minchinton,, A. Mui, and, G. Krystal. 2005. SHIP represses the generation of alternatively activated macrophages. Immunity 23: 361374.
103. Reese, T. A.,, H. E. Liang,, A. M. Tager,, A. D. Luster,, N. van Rooijen,, D. Voehringer, and, R. M. Locksley. 2007. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447: 9296.
104. Roberts, W. K.,, B. E. Laue, and, C. P. Selitrennikoff. 1988. Antifungal proteins from plants. Ann. N. Y. Acad. Sci. 544: 141151.
105. Rodriguez-Sosa, M.,, A. R. Satoskar,, R. Calderon,, L. Gomez-Garcia,, R. Saavedra,, R. Bojalil, and, L. I. Terrazas. 2002. Chronic helminth infection induces alternatively activated macrophages expressing high levels of CCR5 with low interleukin-12 production and Th2-biasing ability. Infect. Immun. 70: 36563664.
106. Rogy, M. A.,, B. G. Beinhauer,, W. Reinisch,, L. Huang, and, P. Pokieser. 2000. Transfer of interleukin-4 and interleukin-10 in patients with severe inflammatory bowel disease of the rectum. Hum. Gene Ther. 11: 17311741.
107. Rotta, G.,, E. W. Edwards,, S. Sangaletti,, C. Bennett,, S. Ronzoni,, M. P. Colombo,, R. M. Steinman,, G. J. Randolph, and, M. Rescigno. 2003. Lipopolysaccharide or whole bacteria block the conversion of inflammatory monocytes into dendritic cells in vivo. J. Exp. Med. 198: 12531263.
108. Rugtveit, J.,, A. Bakka, and, P. Brandtzaeg. 1997. Differential distribution of B7.1 (CD80) and B7.2 (CD86) costimulatory molecules on mucosal macrophage subsets in human inflammatory bowel disease (IBD). Clin. Exp. Immunol. 110: 104113.
109. Saccani, A.,, T. Schioppa,, C. Porta,, S. K. Biswas,, M. Nebuloni,, L. Vago,, B. Bottazzi,, M. P. Colombo,, A. Mantovani, and, A. Sica. 2006. p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 66: 1143211440.
110. Serbina, N. V.,, T. P. Salazar-Mather,, C. A. Biron,, W. A. Kuziel, and, E. G. Pamer. 2003. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19: 5970.
111. Shen, H. M.,, and S. Pervaiz. 2006. TNF receptor superfamily-induced cell death: redox-dependent execution. FASEB J. 20: 15891598.
112. Shortman, K.,, and S. H. Naik. 2007. Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7: 1930.
113. Sica, A.,, and V. Bronte. 2007. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Investig. 117: 11551166.
114. Sica, A.,, A. Saccani,, B. Bottazzi,, N. Polentarutti,, A. Vecchi,, J. van Damme, and, A. Mantovani. 2000. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J. Immunol. 164: 762767.
115. Siegel, C. T.,, K. Schreiber,, S. C. Meredith,, G. B. Beck-Engeser,, D. W. Lancki,, C. A. Lazarski,, Y. X. Fu,, D. A. Rowley, and, H. Schreiber. 2000. Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein. J. Exp. Med. 191: 19451956.
116. Skeel, A.,, T. Yoshimura,, S. D. Showalter,, S. Tanaka,, E. Appella, and, E. J. Leonard. 1991. Macrophage stimulating protein: purification, partial amino acid sequence, and cellular activity. J. Exp. Med. 173: 12271234.
117. Snyder, D. S.,, and E. R. Unanue. 1982. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J. Immunol. 129: 18031805.
118. Spiegel, S.,, and S. Milstien. 2007. Functions of the multifaceted family of sphingosine kinases and some close relatives. J. Biol. Chem. 282: 21252129.
119. Stein, M.,, S. Keshav,, N. Harris, and, S. Gordon. 1992. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176: 287292.
120. Stout, R. D.,, C. Jiang,, B. Matta,, I. Tietzel,, S. K. Watkins, and, J. Suttles. 2005. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J. Immunol. 175: 342349.
121. Stout, R. D.,, and J. Suttles. 2004. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J. Leukoc. Biol. 76: 509513.
122. Sutterwala, F. S.,, G. J. Noel,, P. Salgame, and, D. M. Mosser. 1998. Reversal of proinflammatory responses by ligating the macrophage Fcgamma receptor type I. J. Exp. Med. 188: 217222.
123. Szabo, C.,, G. S. Scott,, L. Virag,, G. Egnaczyk,, A. L. Salzman,, T. P. Shanley, and, G. Hasko. 1998. Suppression of macrophage inflammatory protein (MIP)-1alpha production and collagen-induced arthritis by adenosine receptor agonists. Br. J. Pharmacol. 125: 379387.
124. Tacke, F.,, F. Ginhoux,, C. Jakubzick,, N. van Rooijen,, M. Merad, and, G. J. Randolph. 2006. Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery. J. Exp. Med. 203: 583597.
125. Tacke, F.,, and G. J. Randolph. 2006. Migratory fate and differentiation of blood monocyte subsets. Immunobiology 211: 609618.
126. Tan, E. M.,, and F. D. Shi. 2003. Relative paradigms between autoantibodies in lupus and autoantibodies in cancer. Clin. Exp. Immunol. 134: 169177.
127. Taylor, M. D.,, A. Harris,, M. G. Nair,, R. M. Maizels, and, J. E. Allen. 2006. F4/80+ alternatively activated macrophages control CD4+ T cell hyporesponsiveness at sites peripheral to filarial infection. J. Immunol. 176: 69186927.
128. Trinchieri, G.,, and A. Sher. 2007. Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7: 179190.
129. Tzachanis, D.,, A. Berezovskaya,, L. M. Nadler, and, V. A. Boussiotis. 2002. Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses. Blood 99: 14651473.
130. van Furth, R.,, and Z. A. Cohn. 1968. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128: 415435.
131. Van Ginderachter, J. A.,, K. Movahedi,, G. G. Hassanzadeh,, S. Meerschaut,, A. Beschin,, G. Raes, and, P. De Baetseller. 2006. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology 211: 487501.
132. van Kooten, C.,, and J. Banchereau. 2000. CD40-CD40 ligand. J. Leukoc. Biol. 67: 217.
133. Varol, C.,, L. Landsman,, D. K. Fogg,, L. Greenshtein,, B. Gildor,, R. Margalit,, V. Kalchenko,, F. Geissmann, and, S. Jung. 2007. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204: 171180.
134. Verreck, F. A.,, T. de Boer,, D. M. Langenberg,, M. A. Hoeve,, M. Kramer,, E. Vaisberg,, R. Kastelein,, A. Kolk,, R. de Waal-Malefyt, and, T. H. Ottenhoff. 2004. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc. Natl. Acad. Sci. USA 101: 45604565.
135. Villadangos, J. A. 2007. Hold on, the monocytes are coming! Immunity 26: 390392.
136. Volkman, A.,, and F. M. Collins. 1974. The cytokinetics of monocytosis in acute salmonella infection in the rat. J. Exp. Med. 139: 264277.
137. Waltz, S. E.,, L. Eaton,, K. Toney-Earley,, K. A. Hess,, B. E. Peace,, J. R. Ihlendorf,, M. H. Wang,, K. H. Kaestner, and, S. J. Degen. 2001. Ron-mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses. J. Clin. Investig. 108: 567576.
138. Wang, I. M.,, C. Contursi,, A. Masumi,, X. Ma,, G. Trinchieri, and, K. Ozato. 2000. An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165: 271279.
139. Wang, J.,, R. A. Anders,, Y. Wang,, J. R. Turner,, C. Abraham,, K. Pfeffer, and, Y. X. Fu. 2005. The critical role of LIGHT in promoting intestinal inflammation and Crohn’s disease. J. Immunol. 174: 81738182.
140. Wang, J.,, and Y. X. Fu. 2004. The role of LIGHT in T cell-mediated immunity. Immunol. Res. 30: 201214.
141. Wang, J.,, and Y. X. Fu. 2005. Tumor necrosis factor family members and inflammatory bowel disease. Immunol. Rev. 204: 144155.
142. Wang, M. H.,, C. Ronsin,, M. C. Gesnel,, L. Coupey,, A. Skeel,, E. J. Leonard, and, R. Breathnach. 1994. Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science 266: 117119.
143. Wang, M. H.,, A. Skeel, and, E. J. Leonard. 1996. Proteolytic cleavage and activation of pro-macrophage-stimulating protein by resident peritoneal macrophage membrane proteases. J. Clin. Invest. 97: 720727.
144. Ware, C. F. 2005. Network communications: lymphotoxins, LIGHT, and TNF. Annu. Rev. Immunol. 23: 787819.
145. Weber, C.,, K. U. Belge,, P. von Hundelshausen,, G. Draude,, B. Steppich,, M. Mack,, M. Frankenberger,, K. S. Weber, and, H. W. Ziegler-Heitbrock. 2000. Differential chemokine receptor expression and function in human monocyte sub-populations. J. Leukoc. Biol. 67: 699704.
146. Whitelaw, D. M. 1972. Observations on human monocyte kinetics after pulse labeling. Cell Tissue Kinet. 5: 311317.
147. Wood, K. J.,, and B. Sawitzki. 2006. Interferon gamma: a crucial role in the function of induced regulatory T cells in vivo. Trends Immunol. 27: 183187.
148. Wynn, T. A. 2003. IL-13 effector functions. Annu. Rev. Immunol. 21: 425456.
149. Xu, X.,, and X. Gao. 2004. Immunological responses against SARS-coronavirus infection in humans. Cell Mol. Immunol. 1: 119122.
150. Yang, Z.,, D. M. Mosser, and, X. Zhang. 2007. Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J. Immunol. 178: 10771085.
151. Yen, D.,, J. Cheung,, H. Scheerens,, F. Poulet,, T. McClanahan,, B. McKenzie,, M. A. Kleinschek,, A. Owyang,, J. Mattson,, W. Blumenschein,, E. Murphy,, M. Sathe,, D. J. Cua,, R. A. Kastelein, and, D. Rennick. 2006. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Investig. 116: 13101316.
152. Young, H. A. 2006. Unraveling the pros and cons of interferon-gamma gene regulation. Immunity 24: 506507.
153. Zhang, X.,, J. P. Edwards, and, D. M. Mosser. 2006. Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J. Immunol. 177: 12821288.
154. Zhu, Z.,, T. Zheng,, R. J. Homer,, Y. K. Kim,, N. Y. Chen,, L. Cohn,, Q. Hamid, and, J. A. Elias. 2004. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304: 16781682.
155. Ziegler-Heitbrock, L. 2007. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J. Leukoc. Biol. 81: 584592.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error