M1 and M2 macrophages: Oracles of health and disease

Critical Reviews in Immunology

Volumn 32, Issue 6, 2012, Pages 463-488

  Mills, Charles D ^a  

^a BioMedical Consultants   (United States)

Author keywords

Atherosclerosis; Autoimmunity; Cancer; Innate immunity; M1; M2; Macrophages; Obesity; Stress

Indexed keywords

ADENOSINE; ADRENALIN; CORTICOTROPIN; EPIDERMAL GROWTH FACTOR; HLA ANTIGEN CLASS 2; HYDROCORTISONE; INTERLEUKIN 1; INTERLEUKIN 6; NITRIC OXIDE; ORNITHINE; PROSTAGLANDIN; STRESS HORMONE; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

ADAPTIVE IMMUNITY; ANTIBODY RESPONSE; ANTIBODY SPECIFICITY; ANTIGEN PRESENTATION; ANTIGEN RECOGNITION; ARTICLE; BODY TEMPERATURE; CANCER INCIDENCE; CELLULAR IMMUNITY; FIBROBLAST; HOMEOSTASIS; IMMUNE RESPONSE; IMMUNOREGULATION; IMMUNOSURVEILLANCE; INNATE IMMUNITY; LYMPH NODE; LYMPH VESSEL; MACROPHAGE; MACROPHAGE M1; MACROPHAGE M2; MICROORGANISM DETECTION; PHAGOCYTOSIS; PRIORITY JOURNAL; SKIN INJURY; T LYMPHOCYTE; WOUND HEALING;

ADAPTIVE IMMUNITY; ANIMALS; APOPTOSIS; ARGININE; AUTOIMMUNITY; CELL DIFFERENTIATION; CELL PROLIFERATION; CYTOKINES; HUMANS; IMMUNITY, INNATE; MACROPHAGES; NITRIC OXIDE; ORNITHINE; TH1-TH2 BALANCE; WOUND HEALING;

EID: 84873743410     PISSN: 10408401     EISSN: None     Source Type: Journal    
DOI: 10.1615/CritRevImmunol.v32.i6.10     Document Type: Article

References (135)

1. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166-73.
2. Mills CD. Macrophage arginine metabolism to ornithine/urea or nitric oxide/citrulline: A life or death issue. Crit Rev Immunol. 2001;21:399-425.
3. Murray PJ, Wynn TA. Protective and Pathogenic Functions of Macrophage Subsets. Nat Rev Immunol. 2011;11:723-37.
4. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750-61.
5. Cassetta L, Cassol E, Poli G. Macrophage Polarization in Health and Disease. SciWorld Journ. 2011;11:2,391-402.
6. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253-68.
7. Morgan AJ, Poland GA. The Jenner Society and the Edward Jenner Museum: tributes to a physician-scientist. Vaccine. 2011;30:152-4.
8. Mills, CD, North RJ, Dye ES. Mechanisms of anti-tumor action of Corynebacterium parvum. II. Potentiated cytolytic T cell response and its tumor-induced suppression. J Exp Med. 1981;154:621-30.
9. Mills CD, North RJ. Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in the recipient. Inhibition by suppressor T cells. J Exp Med. 1983;157:1448-60.
10. Chaudhuri D, Suriano R, Mittelman A, Tiwari RK. Targeting the immune system in cancer. Curr Pharm Biotechnol. 2009;10:166-84.
11. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12:278-87.
12. Soghoian DZ, Streeck H. Cytolytic CD4(+) T cells in viral immunity. Expert Rev Vaccines. 2010;12:1453-63.
13. Metchnikoff E. Immunity in Infective Diseases. Cambridge University Press, New York 1905.
14. Cooper EL. eCAM: Darwin and Metchnikoff. Evid Based Complement Alternat. Med. 2009; 6:421-2.
15. Dzik JM. The ancestry and cumulative evolution of immune reactions. Acta Biochemica Polonica. 2010; 57:443-66.
16. Cooper EL. Evolution of immune systems from self/not self to danger to artificial immune systems (AIS). Physics of Life Reviews. 2010; 7:55-78.
17. Janeway CA.The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today. 1992;13:11-6.
18. Beutler, B.A. TLRs and innate immunity. Blood. 2009;113:1,399-407.
19. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34:637-50.
20. Rosenthal AS, Shevach EM. Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J Exp Med. 1973;138:1,194-212.
21. Unanue ER. Antigen-presenting function of the macrophage. Annu Rev Immunol. 1984; 2:395-428.
22. Mackaness GB. The immunological basis of acquired cellular resistance. J Exp Med. 1964;120:105-20.
23. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyteto-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177:7,303-11.
24. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11:762-74.
25. Goncalves R, Zhan X, Cohen H, Debrabant A, Mosser DM. Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection. J Exp Med. 2011;208:1,253-65.
26. Vogt G, Nathan C. In vitro differentiation of human macrophages with enhanced antimycobacterial activity. J Clin Invest. 2011;121:3,889-901.
27. Sinha P, Clements VK, Ostrand-Rosenberg S. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Ca Res 2005;65:11,743-51.
28. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009; 9:162-74.
29. Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol. 2008;181: 5,829-35.
30. Geissmann F, Gordon S, Hume DA, Mowat AM, Randolph GJ. Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol. 2010; 10:453-60.
31. Hibbs JB, Vavrin Z, Taintor RR. L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol. 1987;138:550-65.
32. Williams-Ashman HG, Canellakis ZN. Polyamines in mammalia biology and medicine. Perspect Biol Med. 1979;22:421-53.
33. Wu G, Morris SM. Arginine metabolism: nitric oxide and beyond. Biochem J. 1998;336:1-17.
34. Morris SM. Arginine Metabolism: Boundaries of Our Knowledge. J Nutr. 2007;137:1,602-9.
35. Morris SM. Recent advances in arginine metabolism: roles and regulation of the arginases. Brit Jour Pharmacol. 2009;157:922-30.
36. Albina JE, Mills CD, Henry WL Jr., Caldwell MD. Temporal expression of different pathways of L-arginine metabolism in healing wounds. J Immunol. 1990;144:3,877-80.
37. Vodovotz Y, Bogdan C, Paik J, Xie, QW, Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor b. J Exp Med. 1993;178:605-13.
38. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145-73.
39. O'Garra, A, Murphy K. Role of cytokines in determining T-lymphocyte function. Curr Opin Immunol. 1994;6:458-66.
40. Hsieh CS, Macatonia SE, O'Garra A, Murphy KM. T cell genetic background determines default T helper phenotype development in vitro. J Exp Med. 1995;181:713-21.
41. Heinzel, FP, Sadick, MD, Holaday BJ, Coffman, RL, Locksley RM. Reciprocal expression of interferon g or interleukin 4 during the resolution or progression of murine leishmaniasis: evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989;169:59-72.
42. Stenger S, Thuring H, Rollinghoff M, Bogdan C. Tissue expression of inducible nitric oxide synthase is closely associated with resistance to Leishmania major. J Exp Med. 1994;180:783-93.
43. Oswald IP, Afroun S, Bray D, Petit JF, Lemaire G. Low response of BALB/c macrophages to priming and activating signals. J Leukocyte Biol. 1992; 52:315-22.
44. Dileepan KN, Page JC, Stechschulte DJ. Direct activation of murine peritoneal macrophages for nitric oxide production and tumor cell killing by interferon g. J Interferon Cytokine Res. 1995;15:387-94.
45. Maliszewski CR. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci USA. 1999; 96:1036-41.
46. Iwasaki A, and Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010; 327:291-5.
47. Gordon, S. Alternative activation of macrophages. Nature Rev Immunol. 2003;3:23-5.
48. Modolell M, Corraliza IM, Link F, Soler G, Eichmann K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol. 1995; 25:1,101-4.
49. Munder M, Eichmann K, Moran JM, Centeno F, Soler G, Modolell M. Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol. 1999;163:3,771-7.
50. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004; 25:677-86.
51. Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004;76:509-13.
52. Stout RD, Watkins SK, Suttles J. Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol. 2009;86:1,105-9.
53. Carrel A, Ebeling AH. The transformation of monocytes into fibroblasts through the action of Rous virus. J Exp Med. 1926;43:461-8.
54. Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A. 2003;100:2,426-31.
55. Pufe T, Petersen W, Fändrich F, Varoga D, Wruck CJ, Mentlein R, Helfenstein A, Hoseas D, Dressel S, Tillmann B, Ruhnke M. Programmable cells or monocytic origin (PCMO): a source of peripheral blood stem cells that generate collagen type-producing chondrocytes. J Orthop Res. 2008;26:304-13.
56. Ungefroren H, Groth S, Hyder A, Thomsen N, Hinz H, Reiling N, Grage-Griebenow E, Held-Feindt J, Schulze M, Nüssler Ak, Fändrich F. The generation of programmable cells of monocytic origin involves partial repression of monocyte/ macrophage markers and reactivation of pluripotency genes. Stem Cells Dev. 2010;11:1,769-80.
57. Aldrich A, Kielian T. Central nervous system fibrosis is associated with fibrocyte-like infiltrates. Am J Pathol. 2011;179:2,952-62.
58. Pace JL, Russell SW. Activation of mouse macrophages for tumor cell killing. I. Quantitative analysis of interactions between lymphokine and lipopolysaccharide. J Immunol. 1981;126:1,863-7.
59. Albina JE, Caldwell MD, Henry WL Jr., Mills CD. Regulation of macrophage functions by L-arginine. J Exp Med. 1989;169:1,021-9.
60. Bogdan, C. Species differences in macrophage NO production are important. Nat Immunol. 2002;3:102.
61. Fang FC, Nathan C. Man is not a mouse: reply. J Leukoc Biol. 2007;81:580.
62. Nathan, C. Role of iNOS in human host defense. Science. 2006;312:1,874-5.
63. Ochoa JB, Bernard AC, O'Brien WE, Griffin MM, Maley ME, Rockich AK, Tsuei BJ, Boulanger BR, Kearney PA, Morris Jr SM Jr. Arginase I Expression and Activity in Human Mononuclear Cells After Injury. Ann Surg. 2001;233:393-9.
64. Nathan C. Role of iNOS in human host defense. Science. 2006;312:1,874-5.
65. Murray PJ, Wynn TA. Obstacles and opportunities for understanding macrophage polarization. J Leukoc Biol. 2011;89:557-63.
66. Weigle WO. Immunological unresponsiveness. Adv Immunol. 1973;16:61-122.
67. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991-1045.
68. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nature Rev Immunol. 2010;10:826-37.
69. Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30:245-57.
70. Stout R. Editorial: Macrophage functional phenotypes: no alternatives in dermal wound healing? J Leuk Biol. 2010; 87:19.
71. Romo N, Magri G, Muntasell A, Heredia G, Baía D, Angulo A, Guma M, López-Botet M. Natural killer cell-mediated response to human cytomegalovirus-infected macrophages is modulated by their functional polarization. J Leuk Biol. 2011;90:717-26.
72. Allam JP, Novak N. Local immunological mechanisms of sublingual immunotherapy. Curr Opin Allergy Clin Immunol. 2011;11:571-8.
73. Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nat Immunol. 2011;12:467-71.
74. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol. 2007; 8:1086-94.
75. Anthony RM, Urban JF Jr, Alem F, Hamed HA, Rozo CT, Boucher JL. Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med. 2006;12:955-60.
76. Mills CD. Molecular basis of "suppressor" macrophages: arginine metabolism via the nitric oxide synthetase pathway. J Immunol. 1991;146:2,719-23.
77. Eisenstein TK, Huang D, Meissler JJ, al-Ramadi B. Macrophage nitric oxide mediates immunosuppression in infectious inflammation. Immunobiology. 1994;191:493-502.
78. Medot-Pirenne M, Heilman M J, Saxena M, McDermott PE, Mills CD. Augmentation of an antitumor CTL response in vivo by inhibition of suppressor macrophage nitric oxide. J Immunol. 1999;163:5,877-82.
79. McEwen BS. Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. European Journal of Pharmacology. 2008; 583:174-85.
80. Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci. 1997; 20:78-84.
81. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease Nat Rev Immunol. 2011;11:775-87.
82. Heffner KL. Neuroendocrine Effects of Stress on Immunity in the Elderly: Implications for Inflammatory Disease. Immunol Allergy Clin North Am. 2011;31:95-108.
83. Radek KA. Antimicrobial anxiety: the impact of stress on antimicrobial immunity. J Leuk Biol. 2010;88:263-77.
84. Moreno B, Jukes JP, Vergara-Irigaray N, Errea O, Villoslada P, Perry VH, Newman TA. Systemic inflammation induces axon injury during brain inflammation. Ann Neur. 2011;70:932-42.
85. Dunn RR. The Wild Life of Our Bodies. Harper Collins, NY, NY. 2011.
86. Nathan C. Epidemic Inflammation: Pondering Obesity. Mol Med. 2008;14:485-92.
87. Mills CD, Shearer J, Evans R, Caldwell MD. Macrophage arginine metabolism and the inhibition or stimulation of cancer. J Immunol. 1992;149:2,709-14.
88. Mills CD, Shearer JD, Caldwell MD. Macrophage arginine metabolism via nitric oxide synthase or arginase equates with immunosurveillance or immunostimulation of cancer. In: Biology of Nitric Oxide. S. Moncada, M.A. Marletta, and J.B. Hibbs, Eds. 1992. London; Chapel Hill: Portland Press.
89. Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumourassociated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol. 2012;167:195-205.
90. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med. 2011;9:216-20.
91. Thomas JA, Badini M. The role of innate immunity in spontaneous regression of cancer. Ind J Cancer. 2011;48:246-51.
92. Burnet FM. Immunological surveillance in neoplasia. Transplant Rev. 1971;7:3-25.
93. Stutman O. Lmmunodepression and malignancy. Adv Cancer Res. 1975; 22:261-422.
94. Stutman O. Spontaneous tumors in nude mice: effect of the viable yellow gene. Exp Cell Biol. 1979; 47:129-35.
95. Watkins SK, Egilmez NK, Suttles J, Stout RD. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol. 2007;178:1357-62.
96. Ohri CM, Shikotra A, Green RH, Waller DA, Bradding P. Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival. Eur Resp J. 2009;33:118-26.
97. Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: Potential targets of anti-cancer therapy. Eur J Cancer. 2006;42:717-27.
98. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007;117:1155-66.
99. Stout RD, Watkins SK, Suttles J. Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol. 2009;86:1,105-09.
100. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650-9.
101. Haddow A. Molecular Repair, wound healing, and carcinogenesis: tumor promotion as possible overhealing. Adv Ca Res. 1972;16:181-284.
102. Sieweke MH, Thompson NL, Sporn MB, Bissell MJ. Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta. Science. 1990;248:1,656-60.
103. Mills CD, Stevens RB, Sutherland DER. Nitric Oxide in autoimmunity and cell transplantation. Transplant Proc. 1994;26:3,348.
104. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871-82.
105. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71-8.
106. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39-51.
107. Gazzaniga S, Bravo AI, Guglielmotti A, van Rooijen N, Maschi F, Vecchi A, Mantovani A, Mordoh J, Wainstok R. Targeting tumorassociated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol. 2007;127:2031-41.
108. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235:442-7.
109. Nucera S, Biziato D, DePalma M. The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int J Dev Biol. 2011;55: 495-503.
110. Alleva DG, Burger CJ, Elgert KD. Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-alpha production. Role of tumorderived IL-10, TGF-beta, and prostaglandin E2. J Immunol. 1994;153:1,674-86.
111. Schwarz R. Melancholia and cancer: changes in the psychosomatic interpretation of cancer from the medico-historical viewpoint. Z Psychosom Med Psychoanal. 1987;33:101-10.
112. Hajishengallis G, Lambris JD. Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol. 2011;11:187-200.
113. El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, König T, Schieicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI. Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nature Immunol. 2008;9:1,399-406.
114. Bronkhorst IHG, Ly LV, Jordanova ES, Vrolijk J. Detection of M2-Macrophages in Uveal Melanoma and Relation with Survival. Invest OphthalVis Sci. 2011;52:643-50.
115. Alleva, DG, Kaser, SB, Beller DI. Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/11 and New Zealand Black/White F1 lupus-prone mice and the Leishmania major-susceptible BALB/c strain. J Immunol 1998;161:6878-84.
116. Wills-Karp M, Nathan A, Page K, Karp CL. New insights into innate immune mechanisms underlying allergenicity. Mucosal Immunol. 2010;3:104-10.
117. Fishbein AB, Fuleihan RL. The hygiene hypothesis revisited: does exposure to infectious agents protect us from allergy? Curr Opin Pediatr. 2012;24:98-102.
118. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002; 347:911-20.
119. Klinman D, Shirota H, Tross D, Sato T, Klaschik S. Synthetic oligonucleotides as modulators of inflammation. J Leuk Biol. 2008;84:958-64.
120. Gupta GK, Agrawal DK. CpG oligodeoxynucleotides as TLR9 agonists: therapeutic application in allergy and asthma. BioDrugs. 2010;24:225-35.
121. Triantafyllopoulou A, Franzke C-W, Seshan SV, Perino G, Kalliolias GD, Ramanujam M, van Rooijen N, Davidson A, Ivashkiv LB. Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. Proc Natl Acad Sci U S A. 2010;107:3,012-7.
122. Coffman RL, Sher A, Seder RA. Vaccine Adjuvants: Putting Innate Immunity to Work. Immunity. 2010;33:492-503.
123. Akira S. Innate immunity and adjuvants. Philos Trans R Soc Lond B Biol Sci. 2011;366:2,748-55.
124. Deshpande G, Rao S, Patole S. Progress in the field of probiotics: year 2011. Curr Opin Gastroenterol. 2011;27:13-8.
125. Shida K, Nanno M, Nagata S. Flexible cytokine production by macrophages and T cells in response to probiotic bacteria: a possible mechanism by which probiotics exert multifunctional immune regulatory activities. Gut Microbes. 2011;2:109-14.
126. Nardin A, Abastado JP. Macrophages and cancer. Front Biosci. 2008;13:3494-505.
127. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474:298-306.
128. Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW, Palmer CD, Wilde J, Foxwell BM, Gloger IS, Sweeting T, Marsh M, Walker AP, Bloom SL, Segal AW. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in disease. J Exp Med. 2009;206:1,883-97.
129. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175-84.
130. Kawanishi N, Yano H, Yokogawa Y, Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fatdiet-induced obese mice. Exerc Immunol Rev. 2010;16:105-18.
131. Stevens RB, Sutherland DER, Ansite JD, Saxena M, Rossini TJ, Levay-Young BK, Hering BJ, Mills CD. Insulin down regulates the iNOS pathway: Nitric Oxide as cause and effect of diabetes? J Immunol. 1997;159:5,329-35.
132. Chawla A, Nguyen KD, Sharon Goh, YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11:738-49.
133. Tinkel J, Hassanain H, Khouri SJ. Cardiovascular antioxidant therapy: a review of supplements, pharmacotherapies, and mechanisms. Cardiol Rev. 2012;20:277-83.
134. Chen AF, Chen DD, Daiber A, Faraci FM, Li H, Rembold CM, Laher I. Free radical biology of the cardiovascular system. Clin Sci. (Lond). 2012;123:73.
135. North RJ. The concept of the activated macrophage. J Immunol. 1978;121:806-9.