Pathogenic Mycobacterium bovis strains differ in their ability to modulate the proinflammatory activation phenotype of macrophages

BMC Microbiology

Elena B Lasunskaia²  Maria Regina D’Império-Lima¹  Verônica Lanes²  Tanara V Peres²  Fabricio M Almeida²  Simone CM Ribeiro²  Eduardo P Amaral¹  Marcelle RM Andrade² 

[1]Department of Immunology, Universidade de São Paulo, São Paulo, 05508-900, Brazil

[2]Laboratory of Biology of Recognition, Universidade Estadual do Norte Fluminense, Campos Rio de Janeiro 28013-602, Brazil

关键词: IL-10;    Interferon-γ;    Macrophage activation phenotype;    Mycobacterium bovis;    Bone marrow- derived macrophages;   

Others  :  1221798
DOI  :  10.1186/1471-2180-12-166

 received in 2012-03-08, accepted in 2012-07-18,  发布年份 2012

【 摘 要 】

Background

Tuberculosis, caused by Mycobacterium tuberculosis or Mycobacterium bovis, remains one of the leading infectious diseases worldwide. The ability of mycobacteria to rapidly grow in host macrophages is a factor contributing to enhanced virulence of the bacteria and disease progression. Bactericidal functions of phagocytes are strictly dependent on activation status of these cells, regulated by the infecting agent and cytokines. Pathogenic mycobacteria can survive the hostile environment of the phagosome through interference with activation of bactericidal responses. To study the mechanisms employed by highly virulent mycobacteria to promote their intracellular survival, we investigated modulating effects of two pathogenic M. bovis isolates and a reference M. tuberculosis H37Rv strain, differing in their ability to multiply in macrophages, on activation phenotypes of the cells primed with major cytokines regulating proinflammatory macrophage activity.

Results

Bone marrow- derived macrophages obtained from C57BL/6 mice were infected by mycobacteria after a period of cell incubation with or without treatment with IFN-γ, inducing proinflammatory type-1 macrophages (M1), or IL-10, inducing anti-inflammatory type-2 cells (M2). Phenotypic profiling of M1 and M2 was then evaluated. The M. bovis strain MP287/03 was able to grow more efficiently in the untreated macrophages, compared with the strains B2 or H37Rv. This strain induced weaker secretion of proinflammatory cytokines, coinciding with higher expression of M2 cell markers, mannose receptor (MR) and arginase-1 (Arg-1). Treatment of macrophages with IFN-γ and infection by the strains B2 and H37Rv synergistically induced M1 polarization, leading to high levels of inducible nitric oxide synthase (iNOS) expression, and reduced expression of the Arg-1. In contrast, the cells infected with the strain MP287/03 expressed high levels of Arg-1 which competed with iNOS for the common substrate arginine, leading to lower levels of NO production.

Conclusions

The data obtained demonstrated that the strain, characterized by increased growth in macrophages, down- modulated classical macrophage activation, through induction of an atypical mixed M1/M2 phenotype.

【 授权许可】

   
2012 Andrade et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Gordon S: Alternative activation of macrophages. Nat Rev Immunol 2003, 3:23-35.
• [2]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, 25:677-686.
• [3]Mosser DM, Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008, 8:958-969.
• [4]Lopez-Castejón G, Baroja-Mazo A, Pelegrín P: Novel macrophage polarization model: from gene expression to identification of new anti-inflammatory molecules. Cell Mol Life Sci 2011, 68:3095-3107.
• [5]Kleinnijenhuis J, Oosting M, Joosten LA, Netea MG, Van Crevel R: Innate immune recognition of Mycobacterium tuberculosis. Clin Dev Immunol 2011, 201(1):405310.
• [6]Ehrt S, Schnappinger D, Bekiranov S, Drenkow J, Shi S, Gingeras TR, Gaasterland T, Schoolnik G, Nathan C: Reprogramming of the macrophage transcriptome in response to interferon- and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J Exp Med 2001, 194:1123-1140.
• [7]Kahnert A, Seiler P, Stein M, Bandermann S, Hahnke K, Mollenkopf H, Kaufmann SH: Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis. Eur J Immunol 2006, 36:631-647.
• [8]Aguilar LD, Zumárraga MJ, Oropeza JR, Gioffré AK, Bernardelli A, Orozco EH, Cataldi AA, Hernández P: Mycobacterium bovis with different genotypes and from different hosts induce dissimilar immunopathological lesions in a mouse model of tuberculosis. Clin Exp Immunol 2009, 57:139-147.
• [9]Meikle V, Bianco MV, Blanco FC, Gioffré A, Garbaccio S, Vagnoni L, Di Rienzo J, Canal A, Bigi F, Cataldi A: Evaluation of pathogenesis caused in cattle and guinea pig by a Mycobacterium bovis strain isolated from wild boar. BMC Vet Res 2011, 12:7-37.
• [10]López B, Aguilar D, Orozco H, Burger M, Espitia C, Ritacco V, Barrera L, Kremer K, Hernandez-Pando R, Huygen K, van Soolingen D: A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clin Exp Immunol 2003, 133:30-37.
• [11]Ordway D, Henao-Tamayo M, Harton M, Palanisamy G, Troudt J, Shanley C, Basaraba RJ, Orme IM: The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation. J Immunol 2007, 179:522-531.
• [12]Park JS, Tamayo MH, Gonzalez-Juarrero M, Orme IM, Ordway DJ: Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages. J Leukoc Biol 2006, 79:80-86.
• [13]Lasunskaia E, Ribeiro SC, Manicheva O, Gomes LL, Suffys PN, Mokrousov I, Ferrazoli L, Andrade MR, Kritski A, Otten T, Kipnis TL, da Silva WD, Vishnevsky B, Oliveira MM, Gomes HM, Baptista IF, Narvskaya O: Emerging multidrug resistant Mycobacterium tuberculosis strains of the Beijing genotype circulating in Russia express a pattern of biological properties associated with enhanced virulence. Microb Infect 2010, 12:467-475.
• [14]Rook GA, Steele J, Ainsworth M, Champion BR: Activation of macrophages to inhibit proliferation of Mycobacterium tuberculosis: comparison of the effects of recombinant gamma-interferon on human monocytes and murine peritoneal macrophages. Immunology 1986, 59:333-338.
• [15]Flesch I, Kaufmann SH: Mycobacterial growth inhibition by interferon-gamma -activated bone marrow macrophages and differential susceptibility among strains of Mycobacterium tuberculosis. J Immunol 1987, 138:4408-4413.
• [16]Nathan CF, Murray HW, Wiebe ME, Rubin BY: Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 1983, 158:670-689.
• [17]Lang R: Tuning of macrophage responses by STAT3-inducing cytokines: molecular mechanisms and consequences in infection. Immunobiology 2005, 210:63-76.
• [18]Silver RF, Li Q, Ellner JJ: Expression of virulence of Mycobacterium tuberculosis within human monocytes: virulence correlates with intracellular growth and induction of tumor necrosis factor alpha but not with evasion of lymphocyte-dependent monocyte effector functions. Infect Immun 1998, 66:1190-1199.
• [19]Lukey PT, Hooker EU: Mycobacterium tuberculosis protocols. In Macrophage Virulence Assays. Edited by Parish T, Stoker NG. Humana Press, Totowa, New Jersey; 2003.
• [20]Redente EF, Higgins DM, Dwyer-Nield LD, Orme IM, Gonzalez JM, Malkinson AM: Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation. J Leukoc Biol 2010, 88:159-168.
• [21]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, 25:1101-1104.
• [22]El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, König T, Schleicher 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. Nat Immunol 2008, 9:1399-1406.
• [23]Schreiber S, Perkins SL, Teitelbaum SL, Chappel J, Stahl PD, Blum JS: Regulation of mouse bone marrow macrophage mannose receptor expression and activation by prostaglandin E and IFN-gamma. J Immunol 1993, 151:4973-4981.
• [24]Torrelles JB, Schlesinger LS: Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host. Tuberculosis 2010, 90:84-93.
• [25]Nigou J, Zelle-Rieser C, Gilleron M, Thurnher M, Puzo G: Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J Immunol 2001, 166:7477-7485.
• [26]Pathak SK, Basu S, Bhattacharyya A, Kundu M, Basu J: Mycobacterium tuberculosis lipoarabinomannan-mediated IRAK-M induction negatively regulates Toll-like receptor-dependent interleukin-12 p40 production in macrophages. J Biol Chem 2005, 280:42794-42800.
• [27]Lowe DM, Redford PS, Wilkinson RJ, O'Garra A, Martineau AR: Neutrophils in tuberculosis: friend or foe? Trends Immunol 2012, 1:14-25.
• [28]Weischenfeldt J, Porse B: Bone Marrow-Derived Macrophages (BMM): Isolation and Applications. Cold Spring Harb Protoc 2008.