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Macrophage polarization and plasticity in health and disease

  • Singapore Immunology Network
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Abstract

The role of myelomonocytic cells like monocytes and macrophages as first line of host defense is well established. Recent understanding of these cells using systems biology, transgenesis and in disease models has brought them to a center stage in orchestrating crucial functions during homeostasis and pathogenesis. Thus, understanding the functional diversity of these cells in health and disease as well as the mechanisms that control these events would be crucial for designing strategies for regulating disease and reinstate homeostasis.

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References

  1. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889–96.

    Article  PubMed  CAS  Google Scholar 

  2. Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004;76(3):509–13.

    Article  PubMed  CAS  Google Scholar 

  3. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;17(72):219–46.

    Article  CAS  Google Scholar 

  4. Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9(4):259–70.

    Article  PubMed  CAS  Google Scholar 

  5. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.

    Article  PubMed  CAS  Google Scholar 

  6. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593–604.

    Article  PubMed  CAS  Google Scholar 

  7. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55.

    Article  PubMed  CAS  Google Scholar 

  8. Mantovani A. From phagocyte diversity and activation to probiotics: back to Metchnikoff. Eur J Immunol. 2008;38(12):3269–73.

    Article  PubMed  CAS  Google Scholar 

  9. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177(10):7303–11.

    PubMed  CAS  Google Scholar 

  10. Grohmann U, Bronte V. Control of immune response by amino acid metabolism. Immunol Rev. 2010;236:243–64.

    Article  PubMed  CAS  Google Scholar 

  11. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010;70(1):68–77.

    Article  PubMed  CAS  Google Scholar 

  12. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol. 2010;185(1):605–14.

    Article  PubMed  CAS  Google Scholar 

  13. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, Chawla A. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab. 2006;4(1):13–24.

    Article  PubMed  CAS  Google Scholar 

  14. Cairo G, Recalcati S, Mantovani A, Locati M. Iron trafficking and metabolism in macrophages: contribution to the polarized phenotype. Trends Immunol. 2011;32(6):241–7.

    Article  PubMed  CAS  Google Scholar 

  15. Murata Y, Shimamura T, Hamuro J. The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. Int Immunol. 2002;14(2):201–12.

    Article  PubMed  CAS  Google Scholar 

  16. Loke P, Nair MG, Parkinson J, Guiliano D, Blaxter M, Allen JE. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 2002;3(1):7.

    Article  PubMed  Google Scholar 

  17. Biswas SK, Sica A, Lewis CE. Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol. 2008;180(4):2011–7.

    PubMed  CAS  Google Scholar 

  18. Gustafsson C, Mjosberg J, Matussek A, Geffers R, Matthiesen L, Berg G, Sharma S, Buer J, Ernerudh J. Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS ONE. 2008;3(4):e2078.

    Article  PubMed  CAS  Google Scholar 

  19. Shaul ME, Bennett G, Strissel KJ, Greenberg AS, Obin MS. Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet–induced obesity in mice. Diabetes. 2010;59(5):1171–81.

    Article  PubMed  CAS  Google Scholar 

  20. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.

    Article  PubMed  CAS  Google Scholar 

  21. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki S, Cumano A, Lauvau G, Geissmann F. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317(5838):666–70.

    Article  PubMed  CAS  Google Scholar 

  22. Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA. Possible new role for NF-kappaB in the resolution of inflammation. Nat Med. 2001;7(12):1291–7.

    Article  PubMed  CAS  Google Scholar 

  23. Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, Oh SF, Spite M. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J Exp Med. 2009;206(1):15–23.

    Article  PubMed  CAS  Google Scholar 

  24. Schif-Zuck S, Gross N, Assi S, Rostoker R, Serhan CN, Ariel A. Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids. Eur J Immunol. 2011;41(2):366–79.

    Article  PubMed  CAS  Google Scholar 

  25. Stables MJ, Shah S, Camon EB, Lovering RC, Newson J, Bystrom J, Farrow S, Gilroy DW. Transcriptomic analyses of murine resolution-phase macrophages. Blood. 2011;118(26):192–208.

    Article  CAS  Google Scholar 

  26. Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O’Neill LA, Perretti M, Rossi AG, Wallace JL. Resolution of inflammation: state of the art, definitions and terms. Faseb J. 2007;21(2):325–32.

    Article  PubMed  CAS  Google Scholar 

  27. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175–84.

    Article  PubMed  CAS  Google Scholar 

  28. Rae F, Woods K, Sasmono T, Campanale N, Taylor D, Ovchinnikov DA, Grimmond SM, Hume DA, Ricardo SD, Little MH. Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter. Dev Biol. 2007;308(1):232–46.

    Article  PubMed  CAS  Google Scholar 

  29. Weigert A, Johann AM, von Knethen A, Schmidt H, Geisslinger G, Brune B. Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood. 2006;108(5):1635–42.

    Article  PubMed  CAS  Google Scholar 

  30. Ji RC. Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis. Cell Mol Life Sci. 2011;69(6):897–914.

    Article  PubMed  CAS  Google Scholar 

  31. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145(3):341–55.

    Article  PubMed  CAS  Google Scholar 

  32. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66(23):11238–46.

    Article  PubMed  CAS  Google Scholar 

  33. Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193(6):727–40.

    Article  PubMed  CAS  Google Scholar 

  34. Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, MacDonald AS, Allen JE. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011;332(6035):1284–8.

    Article  PubMed  CAS  Google Scholar 

  35. Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol. 2011;28(6):275–97.

    Article  CAS  Google Scholar 

  36. Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, Ferrante AW Jr. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest. 2010;120(10):3466–79.

    Article  PubMed  CAS  Google Scholar 

  37. Clementi AH, Gaudy AM, van Rooijen N, Pierce RH, Mooney RA. Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim Biophys Acta. 2009;1792(11):1062–72.

    Article  PubMed  CAS  Google Scholar 

  38. Corna G, Campana L, Pignatti E, Castiglioni A, Tagliafico E, Bosurgi L, Campanella A, Brunelli S, Manfredi AA, Apostoli P, Silvestri L, Camaschella C, Rovere-Querini P. Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica. 2010;95(11):1814–22.

    Article  PubMed  CAS  Google Scholar 

  39. Recalcati S, Locati M, Marini A, Santambrogio P, Zaninotto F, De Pizzol M, Zammataro L, Girelli D, Cairo G. Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol. 2010;40(3):824–35.

    Article  PubMed  CAS  Google Scholar 

  40. Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, Hainzl A, Schatz S, Qi Y, Schlecht A, Weiss JM, Wlaschek M, Sunderkotter C, Scharffetter-Kochanek K. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest. 2011;121(3):985–97.

    Article  PubMed  CAS  Google Scholar 

  41. Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev. 2004;3(5):401–16.

    Article  CAS  Google Scholar 

  42. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35.

    Article  PubMed  CAS  Google Scholar 

  43. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nat Med. 2009;15(5):496–7.

    Article  PubMed  CAS  Google Scholar 

  44. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30(10):475–87.

    Article  PubMed  CAS  Google Scholar 

  45. Cavaillon JM, Adib-Conquy M. Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care (London, England). 2006;10(5):233.

    Article  Google Scholar 

  46. Adib-Conquy M, Adrie C, Moine P, Asehnoune K, Fitting C, Pinsky MR, Dhainaut JF, Cavaillon JM. NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance. Am J Respir Crit Care Med. 2000;162(5):1877–83.

    PubMed  CAS  Google Scholar 

  47. Dobrovolskaia MA, Vogel SN. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect. 2002;4(9):903–14.

    Article  PubMed  CAS  Google Scholar 

  48. Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447(7147):972–8.

    PubMed  CAS  Google Scholar 

  49. del Fresno C, Garcia-Rio F, Gomez-Pina V, Soares-Schanoski A, Fernandez-Ruiz I, Jurado T, Kajiji T, Shu C, Marin E, Gutierrez del Arroyo A, Prados C, Arnalich F, Fuentes-Prior P, Biswas SK, Lopez-Collazo E. Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: demonstration in isolated monocytes from cystic fibrosis patients. J Immunol. 2009;182(10):6494–507.

    Article  PubMed  CAS  Google Scholar 

  50. Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Natoli G, De Baetselier P, Mantovani A, Sica A. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A. 2009;106(35):14978–83.

    Article  PubMed  CAS  Google Scholar 

  51. Pena OM, Pistolic J, Raj D, Fjell CD, Hancock RE. Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells. J Immunol. 2011;186(12):7243–54.

    Article  PubMed  CAS  Google Scholar 

  52. Cavaillon JM, Adrie C, Fitting C, Adib-Conquy M. Endotoxin tolerance: is there a clinical relevance? J Endotoxin Res. 2003;9(2):101–7.

    PubMed  CAS  Google Scholar 

  53. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.

    Article  PubMed  CAS  Google Scholar 

  54. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.

    Article  PubMed  CAS  Google Scholar 

  55. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–12.

    Article  PubMed  CAS  Google Scholar 

  56. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.

    Article  PubMed  CAS  Google Scholar 

  57. Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol. 1992;148(4):1280–5.

    PubMed  CAS  Google Scholar 

  58. Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, Bottazzi B, Doni A, Vincenzo B, Pasqualini F, Vago L, Nebuloni M, Mantovani A, Sica A. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood. 2006;107(5):2112–22.

    Article  PubMed  CAS  Google Scholar 

  59. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, Mantovani A. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol. 2000;164(2):762–7.

    PubMed  CAS  Google Scholar 

  60. Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR. “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med. 2008;205(6):1261–8.

    Article  PubMed  CAS  Google Scholar 

  61. Stout RD, Watkins SK, Suttles J. Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol. 2009;86(5):1105–9.

    Article  PubMed  CAS  Google Scholar 

  62. Ojalvo LS, King W, Cox D, Pollard JW. High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors. Am J Pathol. 2009;174(3):1048–64.

    Article  PubMed  CAS  Google Scholar 

  63. Ghassabeh GH, De Baetselier P, Brys L, Noel W, Van Ginderachter JA, Meerschaut S, Beschin A, Brombacher F, Raes G. Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo during different pathologies. Blood. 2006;108(2):575–83.

    Article  PubMed  CAS  Google Scholar 

  64. Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) Monocytes. Cancer Res. 2010;70(14):5728–39.

    Article  PubMed  CAS  Google Scholar 

  65. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–59.

    Article  PubMed  CAS  Google Scholar 

  66. De Palma M, Venneri MA, Galli R, Galli R, Sergi LS, Politi LS, Sampaolesi M, Naldini L. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8(3):211–26.

    Article  PubMed  CAS  Google Scholar 

  67. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475(7355):222–5.

    Article  PubMed  CAS  Google Scholar 

  68. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74.

    Article  PubMed  CAS  Google Scholar 

  69. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–7.

    Article  PubMed  CAS  Google Scholar 

  70. Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem. 2007;282(48):35279–92.

    Article  PubMed  CAS  Google Scholar 

  71. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12(5):408–15.

    Article  PubMed  CAS  Google Scholar 

  72. Masters SL, Latz E, O’Neill LA. The inflammasome in atherosclerosis and type 2 diabetes. Sci Transl Med 2011;3(81):81 (ps17).

    Google Scholar 

  73. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17(2):179–88.

    Article  PubMed  CAS  Google Scholar 

  74. Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, Mahabeleshwar GH, Dalmas E, Venteclef N, Flask CA, Kim J, Doreian BW, Lu KQ, Kaestner KH, Hamik A, Clement K, Jain MK. Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest. 2011;121(7):2736–49.

    Article  PubMed  CAS  Google Scholar 

  75. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Matsuyama T, Yui K, Tsujimura T, Standley DM, Nakanishi K, Nakai K, Akira S. The JMJD3-IRF4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 2010;11(10):936–44.

    Article  PubMed  CAS  Google Scholar 

  76. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11(11):750–61.

    Article  PubMed  CAS  Google Scholar 

  77. Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F, Venturini E, Gregory L, Lonie L, Chew A, Wei CL, Ragoussis J, Natoli G. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity. 2010;32(3):317–28.

    Article  PubMed  CAS  Google Scholar 

  78. De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, Bucci G, Caganova M, Notarbartolo S, Casola S, Testa G, Sung WK, Wei CL, Natoli G. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. Embo J. 2009;28(21):3341–52.

    Article  PubMed  CAS  Google Scholar 

  79. Chawla A. Control of macrophage activation and function by PPARs. Circ Res. 2010;106(10):1559–69.

    Article  PubMed  CAS  Google Scholar 

  80. Bohuslav J, Kravchenko VV, Parry GC, Erlich JH, Gerondakis S, Mackman N, Ulevitch RJ. Regulation of an essential innate immune response by the p50 subunit of NF-kappaB. J Clin Invest. 1998;102(9):1645–52.

    Article  PubMed  CAS  Google Scholar 

  81. Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, Bottazzi B, Colombo MP, Mantovani A, Sica A. p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 2006;66(23):11432–40.

    Article  PubMed  CAS  Google Scholar 

  82. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med. 2005;11(2):191–8.

    Article  PubMed  CAS  Google Scholar 

  83. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540–50.

    Article  PubMed  CAS  Google Scholar 

  84. O’Neill LA. How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol. 2006;18(1):3–9.

    Article  PubMed  CAS  Google Scholar 

  85. Colonna M. TLR pathways and IFN-regulatory factors: to each its own. Eur J Immunol. 2007;37(2):306–9.

    Article  PubMed  CAS  Google Scholar 

  86. Kawai T, Akira S. Toll-like receptor downstream signaling. Arthritis Res Ther. 2005;7(1):12–9.

    Article  PubMed  CAS  Google Scholar 

  87. Ozato K, Tsujimura H, Tamura T. Toll-like receptor signaling and regulation of cytokine gene expression in the immune system. BioTechniques. 2002;Suppl:66-8, 70, 2 passim.

  88. Ohmori Y, Hamilton TA. Requirement for STAT1 in LPS-induced gene expression in macrophages. J Leukoc Biol. 2001;69(4):598–604.

    PubMed  CAS  Google Scholar 

  89. Vakkila J, Demarco RA, Lotze MT. Coordinate NF-kappaB and STAT1 activation promotes development of myeloid type 1 dendritic cells. Scand J Immunol. 2008;67(3):260–9.

    Article  PubMed  CAS  Google Scholar 

  90. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol. 2001;19:623–55.

    Article  PubMed  CAS  Google Scholar 

  91. Jiang H, Harris MB, Rothman P. IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol. 2000;105(6 Pt 1):1063–70.

    Article  PubMed  CAS  Google Scholar 

  92. Donnelly RP, Dickensheets H, Finbloom DS. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res. 1999;19(6):563–73.

    Article  PubMed  CAS  Google Scholar 

  93. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447(7148):1116–20.

    Article  PubMed  CAS  Google Scholar 

  94. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, Lee CH. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7(6):485–95.

    Article  PubMed  CAS  Google Scholar 

  95. Eguchi J, Wang X, Yu S, Kershaw EE, Chiu PC, Dushay J, Estall JL, Klein U, Maratos-Flier E, Rosen ED. Transcriptional control of adipose lipid handling by IRF4. Cell Metab. 2011;13(3):249–59.

    Article  PubMed  CAS  Google Scholar 

  96. Shirey KA, Pletneva LM, Puche AC, Keegan AD, Prince GA, Blanco JC, Vogel SN. Control of RSV-induced lung injury by alternatively activated macrophages is IL-4R alpha-, TLR4-, and IFN-beta-dependent. Mucosal Immunol. 2010;3(3):291–300.

    Article  PubMed  CAS  Google Scholar 

  97. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007;131(6):1124–36.

    Article  PubMed  CAS  Google Scholar 

  98. Escoll P, del Fresno C, Garcia L, Valles G, Lendinez MJ, Arnalich F, Lopez-Collazo E. Rapid up-regulation of IRAK-M expression following a second endotoxin challenge in human monocytes and in monocytes isolated from septic patients. Biochem Biophys Res Commun. 2003;311(2):465–72.

    Article  PubMed  CAS  Google Scholar 

  99. Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr, Medzhitov R, Flavell RA. IRAK-M is a negative regulator of toll-like receptor signaling. Cell. 2002;110(2):191–202.

    Article  PubMed  CAS  Google Scholar 

  100. Lopez-Collazo E, Fuentes-Prior P, Arnalich F, del Fresno C. Pathophysiology of interleukin-1 receptor-associated kinase-M: implications in refractory state. Curr Opin Infect Dis. 2006;19(3):237–44.

    Article  PubMed  CAS  Google Scholar 

  101. Liew FY, Xu D, Brint EK, O’Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005;5(6):446–58.

    Article  PubMed  CAS  Google Scholar 

  102. Rauh MJ, Ho V, Pereira C, Sham A, Sly LM, Lam V, Huxham L, Minchinton AI, Mui A, Krystal G. SHIP represses the generation of alternatively activated macrophages. Immunity. 2005;23(4):361–74.

    Article  PubMed  CAS  Google Scholar 

  103. Saccani S, Natoli G. Dynamic changes in histone H3 Lys 9 methylation occurring at tightly regulated inducible inflammatory genes. Genes Dev. 2002;16(17):2219–24.

    Article  PubMed  CAS  Google Scholar 

  104. Saccani S, Pantano S, Natoli G. p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol. 2002;3(1):69–75.

    Article  PubMed  CAS  Google Scholar 

  105. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007;130(6):1083–94.

    Article  PubMed  CAS  Google Scholar 

  106. Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM, Carson WF, Cavassani KA, Li X, Lukacs NW, Hogaboam CM, Dou Y, Kunkel SL. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood. 2009;114(15):3244–54.

    Article  PubMed  CAS  Google Scholar 

  107. Chan C, Li L, McCall CE, Yoza BK. Endotoxin tolerance disrupts chromatin remodeling and NF-kappaB transactivation at the IL-1beta promoter. J Immunol. 2005;175(1):461–8.

    PubMed  CAS  Google Scholar 

  108. El Gazzar M, Yoza BK, Chen X, Garcia BA, Young NL, McCall CE. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance. Mol Cell Biol. 2009;29(7):1959–71.

    Article  PubMed  CAS  Google Scholar 

  109. Barish GD, Yu RT, Karunasiri M, Ocampo CB, Dixon J, Benner C, Dent AL, Tangirala RK, Evans RM. Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. Genes Dev. 2010;24(24):2760–5.

    Article  PubMed  CAS  Google Scholar 

  110. Ostuni R, Natoli G. Transcriptional control of macrophage diversity and specialization. Eur J Immunol. 2011;41(9):2486–90.

    Article  PubMed  CAS  Google Scholar 

  111. Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD. MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2008;9(8):839–45.

    Article  PubMed  CAS  Google Scholar 

  112. O’Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, Paquette RL, Baltimore D. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205(3):585–94.

    Article  PubMed  CAS  Google Scholar 

  113. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103(33):12481–6.

    Article  PubMed  CAS  Google Scholar 

  114. Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA, Croce CM. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol. 2007;179(8):5082–9.

    PubMed  CAS  Google Scholar 

  115. Bazzoni F, Rossato M, Fabbri M, Gaudiosi D, Mirolo M, Mori L, Tamassia N, Mantovani A, Cassatella MA, Locati M. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci U S A. 2009;106(13):5282–7.

    Article  PubMed  CAS  Google Scholar 

  116. Liu Y, Chen Q, Song Y, Lai L, Wang J, Yu H, Cao X, Wang Q. MicroRNA-98 negatively regulates IL-10 production and endotoxin tolerance in macrophages after LPS stimulation. FEBS Lett. 2011;585(12):1963–8.

    Article  PubMed  CAS  Google Scholar 

  117. Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O’Leary JJ, Ruan Q, Johnson DS, Chen Y, O’Neill LA. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2010;11(2):141–7.

    Article  PubMed  CAS  Google Scholar 

  118. Nahid MA, Satoh M, Chan EK. MicroRNA in TLR signaling and endotoxin tolerance. Cell Mol Immunol. 2011;8(5):388–403.

    Article  PubMed  CAS  Google Scholar 

  119. Imtiyaz HZ, Simon MC. Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol. 2010;345:105–20.

    Article  PubMed  CAS  Google Scholar 

  120. Bosco MC, Puppo M, Santangelo C, Anfosso L, Pfeffer U, Fardin P, Battaglia F, Varesio L. Hypoxia modifies the transcriptome of primary human monocytes: modulation of novel immune-related genes and identification of CC-chemokine ligand 20 as a new hypoxia-inducible gene. J Immunol. 2006;177(3):1941–55.

    PubMed  CAS  Google Scholar 

  121. Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK, Harris AL, Johnson RS, Imityaz HZ, Simon MC, Fredlund E, Greten FR, Rius J, Lewis CE. Hypoxia inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood. 2009;114(4):844–59.

    Article  PubMed  CAS  Google Scholar 

  122. Murdoch C, Lewis CE. Macrophage migration and gene expression in response to tumor hypoxia. Int J Cancer. 2005;117(5):701–8.

    Article  PubMed  CAS  Google Scholar 

  123. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;112(5):645–57.

    Article  PubMed  CAS  Google Scholar 

  124. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008;453(7196):807–11.

    Article  PubMed  CAS  Google Scholar 

  125. Nizet V, Johnson RS. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol. 2009;9(9):609–17.

    Article  PubMed  CAS  Google Scholar 

  126. Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, Simon MC. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120(8):2699–714.

    Article  PubMed  CAS  Google Scholar 

  127. Takeda N, O’Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24(5):491–501.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Reuben Harwood for his help during the preparation of this manuscript. The authors are supported by funding from Biomedical Research Council (BMRC), Agency for Science, Technology & Research (A*STAR), Singapore.

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Correspondence to Subhra K. Biswas.

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Biswas, S.K., Chittezhath, M., Shalova, I.N. et al. Macrophage polarization and plasticity in health and disease. Immunol Res 53, 11–24 (2012). https://doi.org/10.1007/s12026-012-8291-9

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