M2b Macrophage Elimination and Improved Resistance of Mice with Chronic Alcohol Consumption to Opportunistic Infections
2014; Elsevier BV; Volume: 185; Issue: 2 Linguagem: Inglês
10.1016/j.ajpath.2014.09.022
ISSN1525-2191
AutoresHideko Ohama, Akira Asai, Ichiaki Ito, Sumihiro Suzuki, Makiko Kobayashi, Kazuhide Higuchi, Fujio Suzuki,
Tópico(s)Immune Cell Function and Interaction
ResumoAlcohol abuse was found to predispose persons to opportunistic infections. In this study, we tried to improve the host antibacterial resistance of chronic alcohol-consuming (CAC) mice to opportunistic infections. Bactericidal macrophages with functions to produce IL-12 and to express mRNAs for CXCL9 and inducible nitric oxide synthase (M1 macrophages) were characterized as the main effector cells in host antibacterial innate immunities against infections with opportunistic pathogens. However, CAC mice were found to be carriers of M2b macrophages [macrophages with functions to produce IL-10 and to express mRNAs for CD163, chemokine ligand (CCL)1, and LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for high-voltage electron microscopy on T cells)], which were inhibitory on macrophage conversion from resident macrophages to M1 macrophages. Under treatment with CCL1 antisense oligodeoxynucleotides, a specific inhibitor of M2b macrophages, CAC mouse macrophages reverted to resident macrophages, and M1 macrophages were induced by a bacterial antigen from macrophages of CAC mice that were previously treated with the oligodeoxynucleotides. Opportunistic infections (enterococcal translocation and Klebsiella pneumonia) in CAC mice were completely controlled by CCL1 antisense oligodeoxynucleotides. These results indicate that certain opportunistic infections in alcoholics are controllable through the modulation of M2b macrophages. Alcohol abuse was found to predispose persons to opportunistic infections. In this study, we tried to improve the host antibacterial resistance of chronic alcohol-consuming (CAC) mice to opportunistic infections. Bactericidal macrophages with functions to produce IL-12 and to express mRNAs for CXCL9 and inducible nitric oxide synthase (M1 macrophages) were characterized as the main effector cells in host antibacterial innate immunities against infections with opportunistic pathogens. However, CAC mice were found to be carriers of M2b macrophages [macrophages with functions to produce IL-10 and to express mRNAs for CD163, chemokine ligand (CCL)1, and LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for high-voltage electron microscopy on T cells)], which were inhibitory on macrophage conversion from resident macrophages to M1 macrophages. Under treatment with CCL1 antisense oligodeoxynucleotides, a specific inhibitor of M2b macrophages, CAC mouse macrophages reverted to resident macrophages, and M1 macrophages were induced by a bacterial antigen from macrophages of CAC mice that were previously treated with the oligodeoxynucleotides. Opportunistic infections (enterococcal translocation and Klebsiella pneumonia) in CAC mice were completely controlled by CCL1 antisense oligodeoxynucleotides. These results indicate that certain opportunistic infections in alcoholics are controllable through the modulation of M2b macrophages. Alcohol abuse is the third-leading preventable cause of death in the United States, resulting in approximately 100,000 deaths each year. In addition, alcohol abuse causes enormous economic burden.1Naimi T.S. Brewer R.D. Mokdad A. Denny C. Serdula M.K. Marks J.S. Binge drinking among US adults.JAMA. 2003; 289: 70-75Crossref PubMed Scopus (791) Google Scholar Epidemiologic and clinical studies have found that alcohol abuse predisposes persons to opportunistic infections.2Moss M. Epidemiology of sepsis: race, sex, and chronic alcohol abuse.Clin Infect Dis. 2005; 41: S490-S497Crossref PubMed Scopus (99) Google Scholar, 3Zhang P. Bagby G.J. Happel K.I. Raasch C.E. Nelson S. Alcohol abuse, immunosuppression, and pulmonary infection.Curr Drug Abuse Rev. 2008; 1: 56-67Crossref PubMed Google Scholar, 4Engelich G. Wright D.G. Hartshornm K.L. Acquired disorders of phagocyte function complicating medical and surgical illnesses.Clin Infect Dis. 2001; 33: 2040-2048Crossref PubMed Scopus (54) Google Scholar, 5Bhatty M. Pruett S.B. Swiatlo E. Nanduri B. Alcohol abuse and Streptococcus pneumoniae infections: consideration of virulence factors and impaired immune responses.Alcohol. 2011; 45: 523-539Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar The most common alcohol-related bacterial infections include i) pneumonia because of infection with Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus, Haemophilus influenza, Legionella pneumoniae, and Mycobacterium tuberculosis4Engelich G. Wright D.G. Hartshornm K.L. Acquired disorders of phagocyte function complicating medical and surgical illnesses.Clin Infect Dis. 2001; 33: 2040-2048Crossref PubMed Scopus (54) Google Scholar, 5Bhatty M. Pruett S.B. Swiatlo E. Nanduri B. Alcohol abuse and Streptococcus pneumoniae infections: consideration of virulence factors and impaired immune responses.Alcohol. 2011; 45: 523-539Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 6Fernández-Solá J. Junqué A. Estruch R. Monforte R. Torres A. Urbano-Márquez A. High alcohol intake as a risk and prognostic factor for community-acquired pneumonia.Arch Intern Med. 1995; 155: 1649-1654Crossref PubMed Scopus (178) Google Scholar, 7Szabo G. Mandrekar P. A recent perspective on alcohol, immunity, and host defense.Alcohol Clin Exp Res. 2009; 33: 220-232Crossref PubMed Scopus (289) Google Scholar; ii) bacterial meningitis because of infection with S. pneumoniae and Listeria monocytogenes8Weisfelt M. de Gans J. van der Ende A. van de Beek D. Community-acquired bacterial meningitis in alcoholic patients.PLoS One. 2010; 5: e9102Crossref PubMed Scopus (27) Google Scholar; and iii) bacterial translocation from gastrointestinal tracts because of the overgrowth of bacteria in the small intestine, mucosal barrier deficiency, and impaired immune defense mechanisms.9Bode C. Bode J.C. Effect of alcohol consumption on the gut.Best Pract Res Clin Gastroenterol. 2003; 17: 575-592Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 10Tabata T. Tani T. Endo Y. Hanasawa K. Bacterial translocation and peptidoglycan translocation by acute ethanol administration.J Gastroenterol. 2002; 37: 726-731Crossref PubMed Scopus (44) Google Scholar Antibiotics are commonly used against these opportunistic infections. In the case of gut-bacterial infections, however, antibiotic chemotherapies often result in abnormal microflora and multiple antibiotic-resistant bacterial generation because of the long treatment duration and large doses of the antibiotics commonly prescribed in these patients. In addition, oral antibiotic treatment frequently causes overgrowth of commensal fungi in the gut and increases plasma concentration of prostaglandin E2, which induces immunosuppression.11Kim Y.G. Udayanga K.G. Totsuka N. Weinberg J.B. Núñez G. Shibuya A. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced2.Cell Host Microbe. 2014; 15: 95-102Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar Thus, continued development of new paradigms to treat infections associated with alcohol abuse is necessary. Because most of the causative pathogens of infections related to alcohol abuse are endogenous flora and because severe infections with these pathogens are not developed in healthy persons,2Moss M. Epidemiology of sepsis: race, sex, and chronic alcohol abuse.Clin Infect Dis. 2005; 41: S490-S497Crossref PubMed Scopus (99) Google Scholar, 3Zhang P. Bagby G.J. Happel K.I. Raasch C.E. Nelson S. Alcohol abuse, immunosuppression, and pulmonary infection.Curr Drug Abuse Rev. 2008; 1: 56-67Crossref PubMed Google Scholar, 4Engelich G. Wright D.G. Hartshornm K.L. Acquired disorders of phagocyte function complicating medical and surgical illnesses.Clin Infect Dis. 2001; 33: 2040-2048Crossref PubMed Scopus (54) Google Scholar, 5Bhatty M. Pruett S.B. Swiatlo E. Nanduri B. Alcohol abuse and Streptococcus pneumoniae infections: consideration of virulence factors and impaired immune responses.Alcohol. 2011; 45: 523-539Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 6Fernández-Solá J. Junqué A. Estruch R. Monforte R. Torres A. Urbano-Márquez A. High alcohol intake as a risk and prognostic factor for community-acquired pneumonia.Arch Intern Med. 1995; 155: 1649-1654Crossref PubMed Scopus (178) Google Scholar, 7Szabo G. Mandrekar P. A recent perspective on alcohol, immunity, and host defense.Alcohol Clin Exp Res. 2009; 33: 220-232Crossref PubMed Scopus (289) Google Scholar, 8Weisfelt M. de Gans J. van der Ende A. van de Beek D. Community-acquired bacterial meningitis in alcoholic patients.PLoS One. 2010; 5: e9102Crossref PubMed Scopus (27) Google Scholar, 9Bode C. Bode J.C. Effect of alcohol consumption on the gut.Best Pract Res Clin Gastroenterol. 2003; 17: 575-592Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 10Tabata T. Tani T. Endo Y. Hanasawa K. Bacterial translocation and peptidoglycan translocation by acute ethanol administration.J Gastroenterol. 2002; 37: 726-731Crossref PubMed Scopus (44) Google Scholar some immune dysfunctions related to alcohol abuse are the underlying reasons for the increased susceptibility of alcoholics to infections. From these facts, we have hypothesized that certain infections associated with alcohol abuse are immunologically controllable. Host antibacterial immune functions are strongly influenced by chronic alcohol consumption.11Kim Y.G. Udayanga K.G. Totsuka N. Weinberg J.B. Núñez G. Shibuya A. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced2.Cell Host Microbe. 2014; 15: 95-102Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 12Szabo G. Consequences of alcohol consumption on host defence.Alcohol Alcohol. 1999; 34: 830-841Crossref PubMed Scopus (371) Google Scholar, 13Siggins R.W. Melvan J.N. Welsh D.A. Bagby G.J. Nelson S. Zhang P. Alcohol suppresses the granulopoietic response to pulmonary Streptococcus pneumoniae infection with enhancement of STAT3 signaling.J Immunol. 2011; 186: 4306-4313Crossref PubMed Scopus (38) Google Scholar, 14Bagby G.J. Zhang P. Stoltz D.A. Nelson S. Suppression of the granulocyte colony-stimulating factor response to Escherichia coli challenge by alcohol intoxication.Alcohol Clin Exp Res. 1998; 22: 1740-1745Crossref PubMed Scopus (48) Google Scholar, 15Mørland H. Johnsen J. Bjørneboe A. Bjørneboe G.E. Drevon C.A. Mørland J. Mørland B. Reduced IgG Fc-receptor-mediated phagocytosis in human monocytes isolated from alcoholics.Alcohol Clin Exp Res. 1988; 12: 755-759Crossref PubMed Scopus (15) Google Scholar, 16Bautista A.P. Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis.Front Biosci. 2002; 7: a117-a125PubMed Google Scholar, 17Boé D.M. Richens T.R. Horstmann S.A. Burnham E.L. Janssen W.J. Henson P.M. Moss M. Vandivier R.W. Acute and chronic alcohol exposure impair the phagocytosis of apoptotic cells and enhance the pulmonary inflammatory response.Alcohol Clin Exp Res. 2010; 34: 1723-1732Crossref PubMed Scopus (44) Google Scholar, 18Pascual M. Fernández-Lizarbe S. Guerri C. Role of TLR4 in ethanol effects on innate and adaptive immune responses in peritoneal macrophages.Immunol Cell Biol. 2011; 89: 716-727Crossref PubMed Scopus (44) Google Scholar, 19Zisman D.A. Strieter R.M. Kunkel S.L. Tsai W.C. Wilkowski J.M. Bucknell K.A. Standiford T.J. Ethanol feeding impairs innate immunity and alters the expression of Th1- and Th2-phenotype cytokines in murine Klebsiella pneumonia.Alcohol Clin Exp Res. 1998; 22: 621-627Crossref PubMed Scopus (69) Google Scholar, 20Domínguez-Santalla M.J. Vidal C. Viñuela J. Pérez L.F. González-Quintela A. Increased serum IgE in alcoholics: relationship with Th1/Th2 cytokine production by stimulated blood mononuclear cells.Alcohol Clin Exp Res. 2001; 25: 1198-1205Crossref PubMed Scopus (55) Google Scholar, 21Liu W. Li J. Tian W. Xu T. Zhang Z. Chronic alcohol consumption induces cardiac remodeling in mice from Th1 or Th2 background.Exp Mol Pathol. 2011; 91: 761-767Crossref PubMed Scopus (14) Google Scholar, 22Laso F.J. Vaquero J.M. Almeida J. Marcos M. Orfao A. Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells.Alcohol Clin Exp Res. 2007; 31: 846-854Crossref PubMed Scopus (64) Google Scholar, 23Pan H.N. Sun R. Jaruga B. Hong F. Kim W.H. Gao B. Chronic ethanol consumption inhibits hepatic natural killer cell activity and accelerates murine cytomegalovirus-induced hepatitis.Alcohol Clin Exp Res. 2006; 30: 1615-1623Crossref PubMed Scopus (50) Google Scholar, 24Laso F.J. Lapeña P. Madruga J.I. SanMiguel J.F. Orfao A. Iglesias M.C. Alvarez-Mon M. Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake.Alcohol Clin Exp Res. 1997; 21: 1226-1231PubMed Google Scholar, 25Starkenburg S. Munroe M.E. Waltenbaugh C. Early alteration in leukocyte populations and Th1/Th2 function in ethanol-consuming mice.Alcohol Clin Exp Res. 2001; 25: 1221-1230Crossref PubMed Scopus (65) Google Scholar, 26Shellito J.E. quan Zheng M. Ye P. Ruan S. Shean M.K. Kolls J. Effect of alcohol consumption on host release of interleukin-17 during pulmonary infection with Klebsiella pneumoniae.Alcohol Clin Exp Res. 2001; 25: 872-881Crossref PubMed Scopus (39) Google Scholar, 27Latif O. Peterson J.D. Waltenbaugh C. Alcohol-mediated polarization of type 1 and type 2 immune responses.Front Biosci. 2002; 7: a135-a147Crossref PubMed Scopus (25) Google Scholar Observed signs of decreased immune functions include granulopoiesis13Siggins R.W. Melvan J.N. Welsh D.A. Bagby G.J. Nelson S. Zhang P. Alcohol suppresses the granulopoietic response to pulmonary Streptococcus pneumoniae infection with enhancement of STAT3 signaling.J Immunol. 2011; 186: 4306-4313Crossref PubMed Scopus (38) Google Scholar; tissue recruitment of neutrophils,14Bagby G.J. Zhang P. Stoltz D.A. Nelson S. Suppression of the granulocyte colony-stimulating factor response to Escherichia coli challenge by alcohol intoxication.Alcohol Clin Exp Res. 1998; 22: 1740-1745Crossref PubMed Scopus (48) Google Scholar phagocytosis,14Bagby G.J. Zhang P. Stoltz D.A. Nelson S. Suppression of the granulocyte colony-stimulating factor response to Escherichia coli challenge by alcohol intoxication.Alcohol Clin Exp Res. 1998; 22: 1740-1745Crossref PubMed Scopus (48) Google Scholar, 15Mørland H. Johnsen J. Bjørneboe A. Bjørneboe G.E. Drevon C.A. Mørland J. Mørland B. Reduced IgG Fc-receptor-mediated phagocytosis in human monocytes isolated from alcoholics.Alcohol Clin Exp Res. 1988; 12: 755-759Crossref PubMed Scopus (15) Google Scholar, 16Bautista A.P. Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis.Front Biosci. 2002; 7: a117-a125PubMed Google Scholar, 17Boé D.M. Richens T.R. Horstmann S.A. Burnham E.L. Janssen W.J. Henson P.M. Moss M. Vandivier R.W. Acute and chronic alcohol exposure impair the phagocytosis of apoptotic cells and enhance the pulmonary inflammatory response.Alcohol Clin Exp Res. 2010; 34: 1723-1732Crossref PubMed Scopus (44) Google Scholar and Toll-like receptor responses of macrophages18Pascual M. Fernández-Lizarbe S. Guerri C. Role of TLR4 in ethanol effects on innate and adaptive immune responses in peritoneal macrophages.Immunol Cell Biol. 2011; 89: 716-727Crossref PubMed Scopus (44) Google Scholar; and expression and production of type 1 helper T cell (Th1) responses.19Zisman D.A. Strieter R.M. Kunkel S.L. Tsai W.C. Wilkowski J.M. Bucknell K.A. Standiford T.J. Ethanol feeding impairs innate immunity and alters the expression of Th1- and Th2-phenotype cytokines in murine Klebsiella pneumonia.Alcohol Clin Exp Res. 1998; 22: 621-627Crossref PubMed Scopus (69) Google Scholar Decreased macrophage phagocytosis16Bautista A.P. Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis.Front Biosci. 2002; 7: a117-a125PubMed Google Scholar, 17Boé D.M. Richens T.R. Horstmann S.A. Burnham E.L. Janssen W.J. Henson P.M. Moss M. Vandivier R.W. Acute and chronic alcohol exposure impair the phagocytosis of apoptotic cells and enhance the pulmonary inflammatory response.Alcohol Clin Exp Res. 2010; 34: 1723-1732Crossref PubMed Scopus (44) Google Scholar and increased Th2 responses19Zisman D.A. Strieter R.M. Kunkel S.L. Tsai W.C. Wilkowski J.M. Bucknell K.A. Standiford T.J. Ethanol feeding impairs innate immunity and alters the expression of Th1- and Th2-phenotype cytokines in murine Klebsiella pneumonia.Alcohol Clin Exp Res. 1998; 22: 621-627Crossref PubMed Scopus (69) Google Scholar, 20Domínguez-Santalla M.J. Vidal C. Viñuela J. Pérez L.F. González-Quintela A. Increased serum IgE in alcoholics: relationship with Th1/Th2 cytokine production by stimulated blood mononuclear cells.Alcohol Clin Exp Res. 2001; 25: 1198-1205Crossref PubMed Scopus (55) Google Scholar, 21Liu W. Li J. Tian W. Xu T. Zhang Z. Chronic alcohol consumption induces cardiac remodeling in mice from Th1 or Th2 background.Exp Mol Pathol. 2011; 91: 761-767Crossref PubMed Scopus (14) Google Scholar were found in the intestinal mucosa of alcoholics. A decrease in the antigen-presenting abilities of dendritic cells,22Laso F.J. Vaquero J.M. Almeida J. Marcos M. Orfao A. Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells.Alcohol Clin Exp Res. 2007; 31: 846-854Crossref PubMed Scopus (64) Google Scholar perforin/granzyme expression, and interferon-γ production by innate lymphoid cells23Pan H.N. Sun R. Jaruga B. Hong F. Kim W.H. Gao B. Chronic ethanol consumption inhibits hepatic natural killer cell activity and accelerates murine cytomegalovirus-induced hepatitis.Alcohol Clin Exp Res. 2006; 30: 1615-1623Crossref PubMed Scopus (50) Google Scholar, 24Laso F.J. Lapeña P. Madruga J.I. SanMiguel J.F. Orfao A. Iglesias M.C. Alvarez-Mon M. Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake.Alcohol Clin Exp Res. 1997; 21: 1226-1231PubMed Google Scholar and Th1 and Th17 responses25Starkenburg S. Munroe M.E. Waltenbaugh C. Early alteration in leukocyte populations and Th1/Th2 function in ethanol-consuming mice.Alcohol Clin Exp Res. 2001; 25: 1221-1230Crossref PubMed Scopus (65) Google Scholar, 26Shellito J.E. quan Zheng M. Ye P. Ruan S. Shean M.K. Kolls J. Effect of alcohol consumption on host release of interleukin-17 during pulmonary infection with Klebsiella pneumoniae.Alcohol Clin Exp Res. 2001; 25: 872-881Crossref PubMed Scopus (39) Google Scholar, 27Latif O. Peterson J.D. Waltenbaugh C. Alcohol-mediated polarization of type 1 and type 2 immune responses.Front Biosci. 2002; 7: a135-a147Crossref PubMed Scopus (25) Google Scholar were reported in alcoholics. All of these facts were suggested as factors in the increased susceptibility of alcoholics to opportunistic infections. However, it is still unclear how host antibacterial resistance against various types of opportunistic infections is influenced by these immune dysfunctions. The innate immune system is the first line of host defense against invading pathogens.28Medzhitov R. Janeway Jr., C.A. Innate immunity: impact on the adaptive immune response.Curr Opin Immunol. 1997; 9: 4-9Crossref PubMed Scopus (1206) Google Scholar In healthy persons, opportunistic pathogens are usually eliminated at the local infection site by host antibacterial innate immune responses. Macrophages, neutrophils, innate lymphoid cells, dendritic cells, and antimicrobial peptides produced by dermal and intestinal epithelial cells are described as effector cells or factors, of innate immune responses. M1 macrophages are known as main effector cells in host antibacterial innate immunities.29Sester D.P. Stacey K.J. Sweet M.J. Beasley S.J. Cronau S.L. Hume D.L. The actions of bacterial DNA on murine macrophages.J Leukoc Biol. 1999; 66: 542-548PubMed Google Scholar, 30Rothfuchs A.G. Gigliotti D. Palmblad K. Andersson U. Wigzell H. Rottenberg M.E. IFN-α/β-dependent, IFN-γ secretion by bone marrow-derived macrophages controls an intracellular bacterial infection.J Immunol. 2001; 167: 6453-6461Crossref PubMed Scopus (103) Google Scholar, 31Rosenberger C.M. Finlay B.B. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens.Nat Rev Mol Cell Biol. 2003; 4: 385-396Crossref PubMed Scopus (239) Google Scholar, 32Tanaka H. Miyazaki S. Sumiyama Y. Kakiuchi Y. Role of macrophages in a mouse model of postoperative MRSA enteritis.J Surg Res. 2004; 118: 114-121Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 33Tsuda Y. Shigematsu K. Kobayashi M. Herndon D.N. Suzuki F. Role of polymorphonuclear neutrophils on infectious complications stemming from Enterococcus faecalis oral infection in thermally injured mice.J Immunol. 2008; 180: 4133-4138Crossref PubMed Scopus (23) Google Scholar However, M1 macrophages were not easily generated in patients whose M2 macrophages predominated.34Katakura T. Yoshida T. Kobayashi M. Herndon D.N. Suzuki F. Immunological control of methicillin-resistant Staphylococcus aureus (MRSA) infection in an immunodeficient murine model of thermal injuries.Clin Exp Immunol. 2005; 142: 419-425PubMed Google Scholar M2 macrophages inhibit macrophage conversion from resident macrophages to M1 macrophages.35Katakura T. Miyazaki M. Kobayashi M. Herndon D.N. Suzuki F. CCL17 and IL-10 as effectors that enable alternatively activated macrophages to inhibit the generation of classically activated macrophages.J Immunol. 2004; 172: 1407-1413Crossref PubMed Scopus (141) Google Scholar Therefore, hosts who are carriers of M2 macrophages are more susceptible to various opportunistic infections. So far, four different M2 macrophages have been observed: M2a, M2b, M2c, and M2d macrophages.36Mantovani 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: 677-686Abstract Full Text Full Text PDF PubMed Scopus (4493) Google Scholar, 37Edwards J.P. Zhang X. Frauwirth K.A. Mosser D.M. Biochemical and functional characterization of three activated macrophage populations.J Leukoc Biol. 2006; 80: 1298-1307Crossref PubMed Scopus (624) Google Scholar, 38Ferrante C.J. Leibovich S.J. Regulation of macrophage polarization and wound healing.Adv Wound Care (New Rochelle). 2012; 1: 10-16Crossref Google Scholar, 39Wang Q. Ni H. Lan L. Wei X. Xiang R. Wang Y. Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages.Cell Res. 2010; 20: 701-712Crossref PubMed Scopus (114) Google Scholar Each subtype of M2 macrophages is discriminated by their surface antigen expression and cytokine/chemokine-producing profiles. All subtypes of M2 macrophages are equally immunosuppressive. M2d macrophages were observed in tumor-growing sites and accelerate the tumor growth.39Wang Q. Ni H. Lan L. Wei X. Xiang R. Wang Y. Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages.Cell Res. 2010; 20: 701-712Crossref PubMed Scopus (114) Google Scholar In this study, chronic alcohol-consuming (CAC) mice were found to be susceptible to opportunistic infections, and a predominance of M2 macrophages was found in these mice. M2b macrophages isolated from 12-week CAC mice (mice consuming 0.5 mL of 20% ethanol for 12 weeks) reverted to resident macrophages after treatment with chemokine ligand (CCL)1 antisense oligodeoxynucleotides (ODNs). CCL1 is known as an essential chemokine for the maintenance of M2b macrophage properties. Subsequently, M1 macrophages, main effector cells on the host antibacterial resistance, were induced by a bacterial antigen in 12-week CAC mice previously treated with CCL1 antisense ODNs. Enterococcal translocation and Klebsiella pneumonia were not detected in CAC mice depleted of M2b macrophages. These results indicate that certain opportunistic infections in alcoholics are controllable if M2b macrophages, appearing in response to chronic alcohol consumption, can be modulated. CCL1 antisense ODNs are found to be a beneficial weapon for modulating M2b macrophage properties in CAC mice. Nine- to 12-week-old pathogen-free male BALB/c mice, severe combined immunodeficient (SCID) mice, SCID-beige (SCIDbg) mice, nonobese diabetic (NOD)/scid mice, and NOD/scid IL-2Rγnull (NSG) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). SCID mice and NOD/scid mice do not have functional T and B cells, and SCIDbg mice are SCID mice without natural killer (NK) cells. SCIDbgM mice are SCIDbg mice depleted of macrophages, SCIDbgN mice are SCIDbg mice depleted of neutrophils, and SCIDbgNM mice are SCIDbg mice depleted of macrophages and neutrophils. Neutrophils were depleted from SCIDbg mice by whole-body γ-irradiation (4 Gy; 2 days before cell inoculation; SCIDbgN mice).40Tsuda Y. Takahashi H. Kobayashi M. Hanafusa T. Herndon D.N. Suzuki F. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus.Immunity. 2004; 21: 215-226Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar When bone marrow cells or peripheral blood cells taken from SCIDbgN mice were tested morphologically for residual neutrophils after Wright-Giemsa and alkaline phosphatase staining, neutrophils were not detected until 7 days after the irradiation.40Tsuda Y. Takahashi H. Kobayashi M. Hanafusa T. Herndon D.N. Suzuki F. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus.Immunity. 2004; 21: 215-226Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar Macrophages were depleted from SCIDbg mice by treatment with 5 mg/kg gadolinium chloride (i.v.; 24 hours before cell inoculation; SCIDbgM mice).41Hardonk M.J. Dijkhuis F.W. Hulstaert C.E. Koudstaal J. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation.J Leukoc Biol. 1992; 52: 296-302PubMed Google Scholar To deplete both macrophages and neutrophils, SCIDbg mice treated with gadolinium chloride were exposed to whole-body γ-irradiation. SCIDbgMN mice were defined as mice without functional T cells, B cells, NK cells, neutrophils, and macrophages. NSG mice were found to be without functional T cells, B cells, and NK cells.42Piganelli J.D. Martin T. Haskins K. Splenic macrophages from the NOD mouse are defective in the ability to present antigen.Diabetes. 1998; 47: 1212-1218Crossref PubMed Scopus (78) Google Scholar, 43O'Brien B.A. Huang Y. Geng X. Dutz J.P. Finegood D.T. Phagocytosis of apoptotic cells by macrophages from NOD mice is reduced.Diabetes. 2002; 51: 2481-2488Crossref PubMed Scopus (126) Google Scholar, 44Marée A.F. Komba M. Finegood D.T. Edelstein-Keshet L. A quantitative comparison of rates of phagocytosis and digestion of apoptotic cells by macrophages from normal (BALB/c) and diabetes-prone (NOD) mice.J Appl Physiol (1985). 2008; 104: 157-169Crossref PubMed Scopus (40) Google Scholar, 45Takenaka K. Prasolava T.K. Wang J.C. Mortin-Toth S.M. Khalouei S. Gan O.I. Dick J.E. Danska J.S. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells.Nat Immunol. 2007; 8: 1313-1323Crossref PubMed Scopus (371) Google Scholar In addition, NSG mice are carriers of macrophages with defective functions (phagocytosis, digestion, antigen presentation, and activation).42Piganelli J.D. Martin T. Haskins K. Splenic macrophages from the NOD mouse are defective in the ability to present antigen.Diabetes. 1998; 47: 1212-1218Crossref PubMed Scopus (78) Google Scholar, 43O'Brien B.A. Huang Y. Geng X. Dutz J.P. Finegood D.T. Phagocytosis of apoptotic cells by macrophages from NOD mice is reduced.Diabetes. 2002; 51: 2481-2488Crossref PubMed Scopus (126) Google Scholar, 44Marée A.F. Komba M. Finegood D.T. Edelstein-Keshet L. A quantitative comparison of rates of phagocytosis and digestion of apoptotic cells by macrophages from normal (BALB/c) and diabetes-prone (NOD) mice.J Appl Physiol (1985). 2008; 104: 157-169Crossref PubMed Scopus (40) Google Scholar, 45Takenaka K. Prasolava T.K. Wang J.C. Mortin-Toth S.M. Khalouei S. Gan O.I. Dick J.E. Danska J.S. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells.Nat Immunol. 2007; 8: 1313-1323Crossref PubMed Scopus (371) Google Scholar Ethanol (95% v/v) was diluted to 20% (v/v) with physiologic saline. CAC mice were prepared by oral gavage of 0.5 mL of 20% ethanol (0.1 g/d) for 4 to 16 weeks. Control mice received saline in the same fashion. Serum aspartate transaminase and alanine aminotransferase concentrations significantly increased in mice consuming ethanol for 12 weeks compared with concentrations in control mice. However, these concentrations did not increase in mice consuming ethanol for 4 weeks. In addition, the ratio of serum aspartate transaminase to alanine aminotransferase was increased in mice consuming ethanol for 12 weeks, whereas the ratio in mice consuming ethanol for 4 weeks was not di
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