Cellular and Molecular Life Sciences

, Volume 72, Issue 21, pp 4111–4126 | Cite as

Macrophage polarization in pathology

  • Antonio SicaEmail author
  • Marco Erreni
  • Paola Allavena
  • Chiara Porta


Macrophages are cells of the innate immunity constituting the mononuclear phagocyte system and endowed with remarkable different roles essential for defense mechanisms, development of tissues, and homeostasis. They derive from hematopoietic precursors and since the early steps of fetal life populate peripheral tissues, a process continuing throughout adult life. Although present essentially in every organ/tissue, macrophages are more abundant in the gastro-intestinal tract, liver, spleen, upper airways, and brain. They have phagocytic and bactericidal activity and produce inflammatory cytokines that are important to drive adaptive immune responses. Macrophage functions are settled in response to microenvironmental signals, which drive the acquisition of polarized programs, whose extremes are simplified in the M1 and M2 dichotomy. Functional skewing of monocyte/macrophage polarization occurs in physiological conditions (e.g., ontogenesis and pregnancy), as well as in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer) and is now considered a key determinant of disease development and/or regression. Here, we will review evidence supporting a dynamic skewing of macrophage functions in disease, which may provide a basis for macrophage-centered therapeutic strategies.


Macrophage polarization Inflammation Tissue homeostasis Tissue damage Disease 



This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC), Italy; Fondazione Cariplo, Italy; Ministero Università Ricerca (MIUR), Italy; Ministero della Salute; and European Research Council (ERC) Advanced grant NORM.


  1. 1.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5(12):953–964PubMedCrossRefGoogle Scholar
  2. 2.
    Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229(2):176–185PubMedCrossRefGoogle Scholar
  3. 3.
    Biswas SK, Allavena P, Mantovani A (2013) Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol 35(5):585–600PubMedCrossRefGoogle Scholar
  4. 4.
    De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130(6):1083–1094PubMedCrossRefGoogle Scholar
  5. 5.
    Ostuni R, Piccolo V, Barozzi I et al (2013) Latent enhancers activated by stimulation in differentiated cells. Cell 152(1–2):157–171PubMedCrossRefGoogle Scholar
  6. 6.
    Okabe Y, Medzhitov R (2014) Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157(4):832–844PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Xue J, Schmidt SV, Sander J et al (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40(2):274–288PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82PubMedCrossRefGoogle Scholar
  10. 10.
    Shi C, Pamer EG (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11(11):762–774PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Wei S, Nandi S, Chitu V et al (2010) Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol 88(3):495–505PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Martinez FO, Gordon S (2015) The evolution of our understanding of macrophages and translation of findings toward the clinic. Expert Rev Clin Immunol 11(1):5–13PubMedCrossRefGoogle Scholar
  13. 13.
    Vogel DY, Kooij G, Heijnen PD et al (2015) GM-CSF promotes migration of human monocytes across the blood brain barrier. Eur J Immunol 45(6):1808–1819PubMedCrossRefGoogle Scholar
  14. 14.
    Hashimoto D, Chow A, Noizat C et al (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38(4):792–804PubMedCrossRefGoogle Scholar
  15. 15.
    Shibata Y, Berclaz PY, Chroneos ZC, Yoshida M, Whitsett JA, Trapnell BC (2001) GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 15(4):557–567PubMedCrossRefGoogle Scholar
  16. 16.
    Lin HS, Lokeshwar BL, Hsu S (1989) Both granulocyte-macrophage CSF and macrophage CSF control the proliferation and survival of the same subset of alveolar macrophages. J Immunol 142(2):515–519PubMedGoogle Scholar
  17. 17.
    Mantovani A, Sica A, Locati M (2005) Macrophage polarization comes of age. Immunity 23(4):344–346PubMedCrossRefGoogle Scholar
  18. 18.
    Murray PJ, Allen JE, Biswas SK et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41(1):14–20PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Steevels TA, Meyaard L (2011) Immune inhibitory receptors: essential regulators of phagocyte function. Eur J Immunol 41(3):575–587PubMedCrossRefGoogle Scholar
  20. 20.
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35PubMedCrossRefGoogle Scholar
  21. 21.
    Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Novak ML, Koh TJ (2013) Phenotypic transitions of macrophages orchestrate tissue repair. Am J Pathol 183(5):1352–1363PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124(2):263–266PubMedCrossRefGoogle Scholar
  24. 24.
    Ostuni R, Kratochvill F, Murray PJ, Natoli G (2015) Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol 36(4):229–239PubMedCrossRefGoogle Scholar
  25. 25.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686PubMedCrossRefGoogle Scholar
  26. 26.
    Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212(4):435–445PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9(4):259–270PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Klimchenko O, Di Stefano A, Geoerger B et al (2011) Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions. Blood 117(11):3065–3075PubMedCrossRefGoogle Scholar
  29. 29.
    Rae F, Woods K, Sasmono T et al (2007) Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter. Dev Biol 308(1):232–246PubMedCrossRefGoogle Scholar
  30. 30.
    Tagliani E, Shi C, Nancy P, Tay CS, Pamer EG, Erlebacher A (2011) Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. J Exp Med 208(9):1901–1916PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Chorro L, Sarde A, Li M et al (2009) Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J Exp Med 206(13):3089–3100PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Brigitte M, Schilte C, Plonquet A et al (2010) Muscle resident macrophages control the immune cell reaction in a mouse model of notexin-induced myoinjury. Arthritis Rheum 62(1):268–279PubMedCrossRefGoogle Scholar
  33. 33.
    Chazaud B (2014) Macrophages: supportive cells for tissue repair and regeneration. Immunobiology 219(3):172–178PubMedCrossRefGoogle Scholar
  34. 34.
    Swirski FK, Nahrendorf M, Etzrodt M et al (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325(5940):612–616PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Sindrilaru A, Peters T, Wieschalka S et al (2011) An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 121(3):985–997PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Daley JM, Brancato SK, Thomay AA, Reichner JS, Albina JE (2010) The phenotype of murine wound macrophages. J Leukoc Biol 87(1):59–67PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Willenborg S, Lucas T, van Loo G et al (2012) CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120(3):613–625PubMedCrossRefGoogle Scholar
  38. 38.
    Gomez Perdiguero E, Klapproth K, Schulz C et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518(7540):547–551PubMedCrossRefGoogle Scholar
  39. 39.
    Arnold L, Henry A, Poron F et al (2007) Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 204(5):1057–1069PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Bystrom J, Evans I, Newson J et al (2008) Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP. Blood 112(10):4117–4127PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Thomas JA, Pope C, Wojtacha D et al (2011) Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 53(6):2003–2015PubMedCrossRefGoogle Scholar
  42. 42.
    Jung M, Sola A, Hughes J et al (2012) Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2. Kidney Int 81(10):969–982PubMedCrossRefGoogle Scholar
  43. 43.
    Silder A, Heiderscheit BC, Thelen DG, Enright T, Tuite MJ (2008) MR observations of long-term musculotendon remodeling following a hamstring strain injury. Skeletal Radiol 37(12):1101–1109PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Robins SP, Milne G, Duncan A, Davies C, Butt R, Greiling D, James IT (2003) Increased skin collagen extractability and proportions of collagen type III are not normalized after 6 months healing of human excisional wounds. J Invest Dermatol 121(2):267–272PubMedCrossRefGoogle Scholar
  45. 45.
    Mirza R, Koh TJ (2011) Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice. Cytokine 56(2):256–264PubMedCrossRefGoogle Scholar
  46. 46.
    Goren I, Muller E, Schiefelbein D, Christen U, Pfeilschifter J, Muhl H, Frank S (2007) Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages. J Invest Dermatol 127(9):2259–2267PubMedCrossRefGoogle Scholar
  47. 47.
    Mirza RE, Fang MM, Ennis WJ, Koh TJ (2013) Blocking interleukin-1beta induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes 62(7):2579–2587PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Wang Y, Wang YP, Zheng G et al (2007) Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 72(3):290–299PubMedCrossRefGoogle Scholar
  49. 49.
    Hu Y, Zhang H, Lu Y et al (2011) Class A scavenger receptor attenuates myocardial infarction-induced cardiomyocyte necrosis through suppressing M1 macrophage subset polarization. Basic Res Cardiol 106(6):1311–1328PubMedCrossRefGoogle Scholar
  50. 50.
    Murray LA, Rosada R, Moreira AP et al (2010) Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS One 5(3):e9683PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Murray LA, Chen Q, Kramer MS et al (2011) TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol 43(1):154–162PubMedCrossRefGoogle Scholar
  52. 52.
    Vidal B, Serrano AL, Tjwa M et al (2008) Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway. Genes Dev 22(13):1747–1752PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Duffield JS, Forbes SJ, Constandinou CM et al (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115(1):56–65PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Mantovani A, Schioppa T, Porta C, Allavena P, Sica A (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25(3):315–322PubMedCrossRefGoogle Scholar
  55. 55.
    Loges S, Schmidt T, Tjwa M et al (2010) Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood 115(11):2264–2273PubMedCrossRefGoogle Scholar
  56. 56.
    Lin EY, Li JF, Gnatovskiy L et al (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66(23):11238–11246PubMedCrossRefGoogle Scholar
  57. 57.
    Allavena P, Sica A, Garlanda C, Mantovani A (2008) The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev 222:155–161PubMedCrossRefGoogle Scholar
  58. 58.
    Movahedi K, Laoui D, Gysemans C et al (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70(14):5728–5739PubMedCrossRefGoogle Scholar
  59. 59.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570PubMedCrossRefGoogle Scholar
  60. 60.
    Coussens LM, Zitvogel L, Palucka AK (2013) Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339(6117):286–291PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237PubMedCrossRefGoogle Scholar
  62. 62.
    Liu Y, Li PK, Li C, Lin J (2010) Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem 285(35):27429–27439PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Mantovani A, Savino B, Locati M, Zammataro L, Allavena P, Bonecchi R (2010) The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev 21(1):27–39PubMedCrossRefGoogle Scholar
  64. 64.
    Balkwill FR (2012) The chemokine system and cancer. J Pathol 226(2):148–157PubMedCrossRefGoogle Scholar
  65. 65.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedCrossRefGoogle Scholar
  66. 66.
    Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW (2002) The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia 7(2):147–162PubMedCrossRefGoogle Scholar
  67. 67.
    Gazzaniga S, Bravo AI, Guglielmotti A et al (2007) Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol 127(8):2031–2041PubMedCrossRefGoogle Scholar
  68. 68.
    Laoui D, Van Overmeire E, Di Conza G et al (2014) Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 74(1):24–30PubMedCrossRefGoogle Scholar
  69. 69.
    Guo C, Buranych A, Sarkar D, Fisher PB, Wang XY (2013) The role of tumor-associated macrophages in tumor vascularization. Vasc Cell 5(1):20PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 267(2):204–215PubMedCrossRefGoogle Scholar
  71. 71.
    Schioppa T, Uranchimeg B, Saccani A et al (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198(9):1391–1402PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Ceradini DJ, Kulkarni AR, Callaghan MJ et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10(8):858–864PubMedCrossRefGoogle Scholar
  73. 73.
    Muller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56PubMedCrossRefGoogle Scholar
  74. 74.
    Casazza A, Laoui D, Wenes M et al (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24(6):695–709PubMedCrossRefGoogle Scholar
  75. 75.
    Mazzieri R, Pucci F, Moi D et al (2011) Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19(4):512–526PubMedCrossRefGoogle Scholar
  76. 76.
    Nagakawa Y, Aoki T, Kasuya K, Tsuchida A, Koyanagi Y (2002) Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas 24(2):169–178PubMedCrossRefGoogle Scholar
  77. 77.
    Sangaletti S, Di Carlo E, Gariboldi S et al (2008) Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res 68(21):9050–9059PubMedCrossRefGoogle Scholar
  78. 78.
    Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19(11):1423–1437PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555PubMedCrossRefGoogle Scholar
  80. 80.
    Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V (2008) Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 222:162–179PubMedCrossRefGoogle Scholar
  81. 81.
    Liu J, Zhang N, Li Q et al (2011) Tumor-associated macrophages recruit CCR6 + regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice. PLoS One 6(4):e19495PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Lenz G, Wright G, Dave SS et al (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359(22):2313–2323PubMedCrossRefGoogle Scholar
  83. 83.
    Finak G, Bertos N, Pepin F et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518–527PubMedCrossRefGoogle Scholar
  84. 84.
    Beck AH, Espinosa I, Edris B et al (2009) The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res 15(3):778–787PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Steidl C, Lee T, Shah SP et al (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362(10):875–885PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Shaughnessy LM, Swanson JA (2007) The role of the activated macrophage in clearing Listeria monocytogenes infection. Front Biosci 12:2683–2692PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Benoit M, Desnues B, Mege JL (2008) Macrophage polarization in bacterial infections. J Immunol 181(6):3733–3739PubMedCrossRefGoogle Scholar
  88. 88.
    Thompson LJ, Dunstan SJ, Dolecek C et al (2009) Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi. Proc Natl Acad Sci USA 106(52):22433–22438PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Cavaillon JM, Adib-Conquy M (2006) Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care 10(5):233PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG (2011) The pathogenesis of sepsis. Annu Rev Pathol 6:19–48PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Biswas SK, Chittezhath M, Shalova IN, Lim JY (2012) Macrophage polarization and plasticity in health and disease. Immunol Res 53(1–3):11–24PubMedCrossRefGoogle Scholar
  92. 92.
    Porta C, Rimoldi M, Raes G et al (2009) Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci USA 106(35):14978–14983PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Pena OM, Pistolic J, Raj D, Fjell CD, Hancock RE (2011) Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells. J Immunol 186(12):7243–7254PubMedCrossRefGoogle Scholar
  94. 94.
    Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA (2009) The sepsis seesaw: tilting toward immunosuppression. Nat Med 15(5):496–497PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Boomer JS, To K, Chang KC et al (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306(23):2594–2605PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Day J, Friedman A, Schlesinger LS (2009) Modeling the immune rheostat of macrophages in the lung in response to infection. Proc Natl Acad Sci USA 106(27):11246–11251PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Rajaram MV, Brooks MN, Morris JD, Torrelles JB, Azad AK, Schlesinger LS (2010) Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses. J Immunol 185(2):929–942PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Verreck FA, de Boer T, Langenberg DM et al (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(13):4560–4565PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Kahnert A, Seiler P, Stein M, Bandermann S, Hahnke K, Mollenkopf H, Kaufmann SH (2006) Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis. Eur J Immunol 36(3):631–647PubMedCrossRefGoogle Scholar
  100. 100.
    Nicholson S, Bonecini-Almeida Mda G, Lapa e Silva JR et al (1996) Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 183(5):2293–2302PubMedCrossRefGoogle Scholar
  101. 101.
    O’Leary S, O’Sullivan MP, Keane J (2011) IL-10 blocks phagosome maturation in mycobacterium tuberculosis-infected human macrophages. Am J Respir Cell Mol Biol 45(1):172–180PubMedCrossRefGoogle Scholar
  102. 102.
    Rajaram MV, Ni B, Dodd CE, Schlesinger LS (2014) Macrophage immunoregulatory pathways in tuberculosis. Semin Immunol 26(6):471–485PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Gong JH, Zhang M, Modlin RL, Linsley PS, Iyer D, Lin Y, Barnes PF (1996) Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression. Infect Immun 64(3):913–918PubMedCentralPubMedGoogle Scholar
  104. 104.
    Zhang M, Gong J, Iyer DV, Jones BE, Modlin RL, Barnes PF (1994) T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest 94(6):2435–2442PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Parveen N, Varman R, Nair S, Das G, Ghosh S, Mukhopadhyay S (2013) Endocytosis of Mycobacterium tuberculosis heat shock protein 60 is required to induce interleukin-10 production in macrophages. J Biol Chem 288(34):24956–24971PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Odegaard JI, Ricardo-Gonzalez RR, Goforth MH et al (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447(7148):1116–1120PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Mahajan S, Dkhar HK, Chandra V et al (2012) Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARgamma and TR4 for survival. J Immunol 188(11):5593–5603PubMedCrossRefGoogle Scholar
  108. 108.
    Lammas DA, Stober C, Harvey CJ, Kendrick N, Panchalingam S, Kumararatne DS (1997) ATP-induced killing of mycobacteria by human macrophages is mediated by purinergic P2Z(P2X7) receptors. Immunity 7(3):433–444PubMedCrossRefGoogle Scholar
  109. 109.
    Biswas D, Qureshi OS, Lee WY, Croudace JE, Mura M, Lammas DA (2008) ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages. BMC Immunol 9:35PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Canaday DH, Beigi R, Silver RF, Harding CV, Boom WH, Dubyak GR (2002) ATP and control of intracellular growth of mycobacteria by T cells. Infect Immun 70(11):6456–6459PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Dubois-Colas N, Petit-Jentreau L, Barreiro LB et al (2014) Extracellular adenosine triphosphate affects the response of human macrophages infected with Mycobacterium tuberculosis. J Infect Dis 210(5):824–833PubMedCrossRefGoogle Scholar
  112. 112.
    Desai BN, Leitinger N (2014) Purinergic and calcium signaling in macrophage function and plasticity. Front Immunol 5:580PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Sansom FM, Robson SC, Hartland EL (2008) Possible effects of microbial ecto-nucleoside triphosphate diphosphohydrolases on host-pathogen interactions. Microbiol Mol Biol Rev 72(4):765–781 (Table of Contents) PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Graham DY (2015) Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. gastroenterology 148(4):719–731PubMedCrossRefGoogle Scholar
  115. 115.
    Munari F, Fassan M, Capitani N et al (2014) Cytokine BAFF released by Helicobacter pylori-infected macrophages triggers the Th17 response in human chronic gastritis. J Immunol 193(11):5584–5594PubMedCrossRefGoogle Scholar
  116. 116.
    Gobert AP, Verriere T, Asim M et al (2014) Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori. J Immunol 193(6):3013–3022PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Gobert AP, Cheng Y, Wang JY et al (2002) Helicobacter pylori induces macrophage apoptosis by activation of arginase II. J Immunol 168(9):4692–4700PubMedCrossRefGoogle Scholar
  118. 118.
    Lewis ND, Asim M, Barry DP et al (2010) Arginase II restricts host defense to Helicobacter pylori by attenuating inducible nitric oxide synthase translation in macrophages. J Immunol 184(5):2572–2582PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Lewis ND, Asim M, Barry DP et al (2011) Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II. J Immunol 186(6):3632–3641PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Chaturvedi R, Asim M, Hoge S et al (2010) Polyamines impair immunity to Helicobacter pylori by inhibiting l-arginine uptake required for nitric oxide production. Gastroenterology 139(5):1686–1698PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Asim M, Chaturvedi R, Hoge S et al (2010) Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages. J Biol Chem 285(26):20343–20357PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Chaturvedi R, Cheng Y, Asim M et al (2004) Induction of polyamine oxidase 1 by Helicobacter pylori causes macrophage apoptosis by hydrogen peroxide release and mitochondrial membrane depolarization. J Biol Chem 279(38):40161–40173PubMedCrossRefGoogle Scholar
  123. 123.
    Xu H, Chaturvedi R, Cheng Y et al (2004) Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis. Cancer Res 64(23):8521–8525PubMedCrossRefGoogle Scholar
  124. 124.
    El Kasmi KC, Qualls JE, Pesce JT et al (2008) Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9(12):1399–1406PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Van den Bossche J, Lamers WH, Koehler ES et al (2012) Pivotal Advance: Arginase-1-independent polyamine production stimulates the expression of IL-4-induced alternatively activated macrophage markers while inhibiting LPS-induced expression of inflammatory genes. J Leukoc Biol 91(5):685–699PubMedCrossRefGoogle Scholar
  126. 126.
    Chaturvedi R, de Sablet T, Coburn LA, Gobert AP, Wilson KT (2012) Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis. Amino Acids 42(2–3):627–640PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Wang YC, Chen CL, Sheu BS, Yang YJ, Tseng PC, Hsieh CY, Lin CF (2014) Helicobacter pylori infection activates Src homology-2 domain-containing phosphatase 2 to suppress IFN-gamma signaling. J Immunol 193(8):4149–4158PubMedCrossRefGoogle Scholar
  128. 128.
    Straubinger RK, Greiter A, McDonough SP et al (2003) Quantitative evaluation of inflammatory and immune responses in the early stages of chronic Helicobacter pylori infection. Infect Immun 71(5):2693–2703PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    Serrano C, Diaz MI, Valdivia A et al (2007) Relationship between Helicobacter pylori virulence factors and regulatory cytokines as predictors of clinical outcome. Microbes Infect 9(4):428–434PubMedCrossRefGoogle Scholar
  130. 130.
    Mitchell DJ, Huynh HQ, Ceponis PJ, Jones NL, Sherman PM (2004) Helicobacter pylori disrupts STAT1-mediated gamma interferon-induced signal transduction in epithelial cells. Infect Immun 72(1):537–545PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Alfano M, Graziano F, Genovese L, Poli G (2013) Macrophage polarization at the crossroad between HIV-1 infection and cancer development. Arterioscler Thromb Vasc Biol 33(6):1145–1152PubMedCrossRefGoogle Scholar
  132. 132.
    Hong S, Banks WA (2015) Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. Brain Behav Immun 45:1–12PubMedCrossRefGoogle Scholar
  133. 133.
    Zanni MV, Grinspoon SK (2012) HIV-specific immune dysregulation and atherosclerosis. Curr HIV/AIDS Rep 9(3):200–205PubMedCrossRefGoogle Scholar
  134. 134.
    Cassetta L, Kajaste-Rudnitski A, Coradin T et al (2013) M1 polarization of human monocyte-derived macrophages restricts pre and postintegration steps of HIV-1 replication. AIDS 27(12):1847–1856PubMedCrossRefGoogle Scholar
  135. 135.
    Herbein G, Varin A (2010) The macrophage in HIV-1 infection: from activation to deactivation? Retrovirology 7:33PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Williams DW, Eugenin EA, Calderon TM, Berman JW (2012) Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol 91(3):401–415PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Murray CJ, Rosenfeld LC, Lim SS et al (2012) Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 379(9814):413–431PubMedCrossRefGoogle Scholar
  138. 138.
    Porta C, Riboldi E, Sica A (2011) Mechanisms linking pathogens-associated inflammation and cancer. Cancer Lett 305(2):250–262PubMedCrossRefGoogle Scholar
  139. 139.
    Raes G, Beschin A, Ghassabeh GH, De Baetselier P (2007) Alternatively activated macrophages in protozoan infections. Curr Opin Immunol 19(4):454–459PubMedCrossRefGoogle Scholar
  140. 140.
    Gazzinelli RT, Kalantari P, Fitzgerald KA, Golenbock DT (2014) Innate sensing of malaria parasites. Nat Rev Immunol 14(11):744–757PubMedCrossRefGoogle Scholar
  141. 141.
    Cunnington AJ, de Souza JB, Walther M, Riley EM (2012) Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization. Nat Med 18(1):120–127CrossRefGoogle Scholar
  142. 142.
    Lokken KL, Mooney JP, Butler BP et al (2014) Malaria parasite infection compromises control of concurrent systemic non-typhoidal Salmonella infection via IL-10-mediated alteration of myeloid cell function. PLoS Pathog 10(5):e1004049PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Scott JA, Berkley JA, Mwangi I et al (2011) Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet 378(9799):1316–1323PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Takele Y, Abebe T, Weldegebreal T et al (2013) Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection. PLoS Negl Trop Dis 7(1):e1977PubMedCentralPubMedCrossRefGoogle Scholar
  145. 145.
    Porta C, Riboldi E, Totaro MG, Strauss L, Sica A, Mantovani A (2011) Macrophages in cancer and infectious diseases: the ‘good’ and the ‘bad’. Immunotherapy 3(10):1185–1202PubMedCrossRefGoogle Scholar
  146. 146.
    Beschin A, De Baetselier P, Van Ginderachter JA (2013) Contribution of myeloid cell subsets to liver fibrosis in parasite infection. J Pathol 229(2):186–197PubMedCrossRefGoogle Scholar
  147. 147.
    Liu YC, Zou XB, Chai YF, Yao YM (2014) Macrophage polarization in inflammatory diseases. Int J Biol Sci 10(5):520–529PubMedCentralPubMedCrossRefGoogle Scholar
  148. 148.
    Pesce JT, Ramalingam TR, Mentink-Kane MM et al (2009) Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 5(4):e1000371PubMedCentralPubMedCrossRefGoogle Scholar
  149. 149.
    Warmington KS, Boring L, Ruth JH et al (1999) Effect of C-C chemokine receptor 2 (CCR2) knockout on type-2 (schistosomal antigen-elicited) pulmonary granuloma formation: analysis of cellular recruitment and cytokine responses. Am J Pathol 154(5):1407–1416PubMedCentralPubMedCrossRefGoogle Scholar
  150. 150.
    Kim HY, DeKruyff RH, Umetsu DT (2010) The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 11(7):577–584PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Moreira AP, Hogaboam CM (2011) Macrophages in allergic asthma: fine-tuning their pro- and anti-inflammatory actions for disease resolution. J Interferon Cytokine Res 31(6):485–491PubMedCrossRefGoogle Scholar
  152. 152.
    Melgert BN, ten Hacken NH, Rutgers B, Timens W, Postma DS, Hylkema MN (2011) More alternative activation of macrophages in lungs of asthmatic patients. J Allergy Clin Immunol 127(3):831–833PubMedCrossRefGoogle Scholar
  153. 153.
    Veremeyko T, Siddiqui S, Sotnikov I, Yung A, Ponomarev ED (2013) IL-4/IL-13-dependent and independent expression of miR-124 and its contribution to M2 phenotype of monocytic cells in normal conditions and during allergic inflammation. PLoS One 8(12):e81774PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Winkler C, Witte L, Moraw N et al (2014) Impact of endobronchial allergen provocation on macrophage phenotype in asthmatics. BMC Immunol 15:12PubMedCentralPubMedCrossRefGoogle Scholar
  155. 155.
    Kurowska-Stolarska M, Stolarski B, Kewin P et al (2009) IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol 183(10):6469–6477PubMedCrossRefGoogle Scholar
  156. 156.
    Han H, Headley MB, Xu W, Comeau MR, Zhou B, Ziegler SF (2013) Thymic stromal lymphopoietin amplifies the differentiation of alternatively activated macrophages. J Immunol 190(3):904–912PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Soumelis V, Reche PA, Kanzler H et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3(7):673–680PubMedGoogle Scholar
  158. 158.
    Ying S, O’Connor B, Ratoff J et al (2005) Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 174(12):8183–8190PubMedCrossRefGoogle Scholar
  159. 159.
    Lambrecht BN, Hammad H (2015) The immunology of asthma. Nat Immunol 16(1):45–56PubMedCrossRefGoogle Scholar
  160. 160.
    Khanduja KL, Kaushik G, Khanduja S, Pathak CM, Laldinpuii J, Behera D (2011) Corticosteroids affect nitric oxide generation, total free radicals production, and nitric oxide synthase activity in monocytes of asthmatic patients. Mol Cell Biochem 346(1–2):31–37PubMedCrossRefGoogle Scholar
  161. 161.
    Zeiger RS, Schatz M, Zhang F, Crawford WW, Kaplan MS, Roth RM, Chen W (2011) Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma 48(1):8–17PubMedCrossRefGoogle Scholar
  162. 162.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808PubMedCentralPubMedCrossRefGoogle Scholar
  163. 163.
    Grant RW, Dixit VD (2015) Adipose tissue as an immunological organ. Obesity (Silver Spring) 23(3):512–518CrossRefGoogle Scholar
  164. 164.
    Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246PubMedCrossRefGoogle Scholar
  165. 165.
    Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Weisberg SP, Hunter D, Huber R et al (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116(1):115–124PubMedCentralPubMedCrossRefGoogle Scholar
  167. 167.
    Kanda H, Tateya S, Tamori Y et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116(6):1494–1505PubMedCentralPubMedCrossRefGoogle Scholar
  168. 168.
    Kurokawa J, Nagano H, Ohara O, Kubota N, Kadowaki T, Arai S, Miyazaki T (2011) Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue. Proc Natl Acad Sci USA 108(29):12072–12077PubMedCentralPubMedCrossRefGoogle Scholar
  169. 169.
    Cinti S, Mitchell G, Barbatelli G et al (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46(11):2347–2355PubMedCrossRefGoogle Scholar
  170. 170.
    Strissel KJ, Stancheva Z, Miyoshi H et al (2007) Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56(12):2910–2918PubMedCrossRefGoogle Scholar
  171. 171.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117(1):175–184PubMedCentralPubMedCrossRefGoogle Scholar
  172. 172.
    Wang P, Mariman E, Renes J, Keijer J (2008) The secretory function of adipocytes in the physiology of white adipose tissue. J Cell Physiol 216(1):3–13PubMedCrossRefGoogle Scholar
  173. 173.
    Scherer PE (2006) Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55(6):1537–1545PubMedCrossRefGoogle Scholar
  174. 174.
    Halberg N, Wernstedt-Asterholm I, Scherer PE (2008) The adipocyte as an endocrine cell. Endocrinol Metab Clin North Am 37(3):753–768PubMedCentralPubMedCrossRefGoogle Scholar
  175. 175.
    Arner E, Westermark PO, Spalding KL et al (2010) Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes 59(1):105–109PubMedCentralPubMedCrossRefGoogle Scholar
  176. 176.
    Hardy OT, Perugini RA, Nicoloro SM, Gallagher-Dorval K, Puri V, Straubhaar J, Czech MP (2011) Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity. Surg Obes Relat Dis 7(1):60–67PubMedCentralPubMedCrossRefGoogle Scholar
  177. 177.
    Heilbronn LK, Campbell LV (2008) Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 14(12):1225–1230PubMedCrossRefGoogle Scholar
  178. 178.
    Hevener AL, Olefsky JM, Reichart D et al (2007) Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 117(6):1658–1669PubMedCentralPubMedCrossRefGoogle Scholar
  179. 179.
    Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, Ferrante AW Jr (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120(10):3466–3479PubMedCentralPubMedCrossRefGoogle Scholar
  180. 180.
    Pal D, Dasgupta S, Kundu R et al (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18(8):1279–1285PubMedCrossRefGoogle Scholar
  181. 181.
    Lee HM, Kim JJ, Kim HJ, Shong M, Ku BJ, Jo EK (2013) Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62(1):194–204PubMedCentralPubMedCrossRefGoogle Scholar
  182. 182.
    Patel MN, Bernard WG, Milev NB et al (2015) Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. Proc Natl Acad Sci USA 112(2):506–511PubMedCentralPubMedCrossRefGoogle Scholar
  183. 183.
    Morris DL, Cho KW, Delproposto JL et al (2013) Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4 + T cells in mice. Diabetes 62(8):2762–2772PubMedCentralPubMedCrossRefGoogle Scholar
  184. 184.
    Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ (2007) Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 117(1):195–205PubMedCentralPubMedCrossRefGoogle Scholar
  185. 185.
    Yvan-Charvet L, Pagler T, Gautier EL et al (2010) ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328(5986):1689–1693PubMedCentralPubMedCrossRefGoogle Scholar
  186. 186.
    Tacke F, Alvarez D, Kaplan TJ et al (2007) Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 117(1):185–194PubMedCentralPubMedCrossRefGoogle Scholar
  187. 187.
    Peled M, Fisher EA (2014) Dynamic aspects of macrophage polarization during atherosclerosis progression and regression. Front Immunol 5:579PubMedCentralPubMedCrossRefGoogle Scholar
  188. 188.
    Kadl A, Meher AK, Sharma PR et al (2010) Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res 107(6):737–746PubMedCentralPubMedCrossRefGoogle Scholar
  189. 189.
    Hubler MJ, Peterson KR, Hasty AH (2015) Iron homeostasis: a new job for macrophages in adipose tissue? Trends Endocrinol Metab 26(2):101–109PubMedCrossRefGoogle Scholar
  190. 190.
    Recalcati S, Locati M, Marini A et al (2010) Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol 40(3):824–835PubMedCrossRefGoogle Scholar
  191. 191.
    Orr JS, Kennedy A, Anderson-Baucum EK et al (2014) Obesity alters adipose tissue macrophage iron content and tissue iron distribution. Diabetes 63(2):421–432PubMedCentralPubMedCrossRefGoogle Scholar
  192. 192.
    Orozco LD, Kapturczak MH, Barajas B et al (2007) Heme oxygenase-1 expression in macrophages plays a beneficial role in atherosclerosis. Circ Res 100(12):1703–1711PubMedCrossRefGoogle Scholar
  193. 193.
    Jais A, Einwallner E, Sharif O et al (2014) Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell 158(1):25–40PubMedCrossRefGoogle Scholar
  194. 194.
    Marathe C, Bradley MN, Hong C, Chao L, Wilpitz D, Salazar J, Tontonoz P (2009) Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma-/-, PPARdelta-/-, PPARgammadelta-/-, or LXRalphabeta-/- bone marrow. J Lipid Res 50(2):214–224PubMedCentralPubMedCrossRefGoogle Scholar
  195. 195.
    Nguyen KD, Qiu Y, Cui X et al (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480(7375):104–108PubMedCentralPubMedCrossRefGoogle Scholar
  196. 196.
    Qiu Y, Nguyen KD, Odegaard JI et al (2014) Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157(6):1292–1308PubMedCentralPubMedCrossRefGoogle Scholar
  197. 197.
    Perino A, Beretta M, Kilic A et al (2014) Combined inhibition of PI3Kbeta and PI3Kgamma reduces fat mass by enhancing alpha-MSH-dependent sympathetic drive. Sci Signal 7(352):110CrossRefGoogle Scholar
  198. 198.
    Quinn SR, O’Neill LA (2011) A trio of microRNAs that control Toll-like receptor signalling. Int Immunol 23(7):421–425PubMedCrossRefGoogle Scholar
  199. 199.
    Bazzoni F, Rossato M, Fabbri M et al (2009) Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci USA 106(13):5282–5287PubMedCentralPubMedCrossRefGoogle Scholar
  200. 200.
    Liu G, Abraham E (2013) MicroRNAs in immune response and macrophage polarization. Arterioscler Thromb Vasc Biol 33(2):170–177PubMedCentralPubMedCrossRefGoogle Scholar
  201. 201.
    Takeuch O, Akira S (2011) Epigenetic control of macrophage polarization. Eur J Immunol 41(9):2490–2493PubMedCrossRefGoogle Scholar
  202. 202.
    Garofalo RS, Orena SJ, Rafidi K et al (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 112(2):197–208PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Antonio Sica
    • 1
    • 2
    Email author
  • Marco Erreni
    • 2
  • Paola Allavena
    • 2
  • Chiara Porta
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversità del Piemonte Orientale “Amedeo Avogadro”NovaraItaly
  2. 2.Humanitas Clinical and Research CenterMilanItaly

Personalised recommendations