Skip to main content
SpringerLink
Log in

Dying to Live: How the Death Modality of the Infected Macrophage Affects Immunity to Tuberculosis

  • Chapter
  • First Online:
The New Paradigm of Immunity to Tuberculosis

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 783))

Abstract

Virulent Mycobacterium tuberculosis (Mtb) inhibits apoptosis and triggers necrosis of host macrophages to evade innate delay in the initiation of adaptive immunity. Necrosis is a mechanism used by bacteria to exit macrophage, evade the host defenses, and disseminate while apoptosis is associated with diminished pathogen viability. We have recently demonstrated that eicosanoids regulate cell death program of either human or murine macrophages infected with Mtb. We have defined prostaglandin E2 (PGE2) as a pro-apoptotic host lipid mediator which protects against necrosis. In contrast, lipoxin A4 (LXA4) is a pro-necrotic lipid mediator which suppresses PGE2 synthesis, resulting in mitochondrial damage and inhibition of plasma membrane repair mechanisms; this ultimately leads to the induction of necrosis. Thus, the balance between PGE2 and LXA4 determines whether Mtb-infected macrophages undergo apoptosis or necrosis and this balance determines the outcome of infection.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. WHO (2012) World health organization: global tuberculosis control 2010

    Google Scholar 

  2. Behar SM, Martin CJ, Nunes-Alves C, Divangahi M, Remold HG (2011) Lipids, apoptosis, and cross-presentation: links in the chain of host defense against Mycobacterium tuberculosis. Microbes Infect 13:749–756

    Article  PubMed  CAS  Google Scholar 

  3. Dye C, Williams BG (2010) The population dynamics and control of tuberculosis. Science 328:856–861

    Article  PubMed  CAS  Google Scholar 

  4. Kaufmann SH (2001) How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 1:20–30

    Article  PubMed  CAS  Google Scholar 

  5. Chen M, Gan H, Remold HG (2006) A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis. J Immunol 176:3707–3716

    PubMed  CAS  Google Scholar 

  6. Keane J, Remold HG, Kornfeld H (2000) Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J Immunol 164:2016–2020

    PubMed  CAS  Google Scholar 

  7. Hinchey J et al (2007) Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis. J Clin Invest 117:2279–2288

    Article  PubMed  CAS  Google Scholar 

  8. Velmurugan K et al (2007) Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells. PLoS Pathog 3:e110

    Article  PubMed  Google Scholar 

  9. Molloy A, Laochumroonvorapong P, Kaplan G (1994) Apoptosis, but not necrosis, of infected monocytes is coupled with killing of intracellular bacillus Calmette-Guerin. J Exp Med 180:1499–1509

    Article  PubMed  CAS  Google Scholar 

  10. Fratazzi C, Arbeit RD, Carini C, Remold HG (1997) Programmed cell death of Mycobacterium avium serovar 4-infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages. J Immunol 158:4320–4327

    PubMed  CAS  Google Scholar 

  11. Divangahi M et al (2009) Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Nat Immunol 10:899–906

    Article  PubMed  CAS  Google Scholar 

  12. Chen M et al (2008) Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. J Exp Med 205:2791–2801

    Article  PubMed  CAS  Google Scholar 

  13. Constance et al (2012) Efferocytosis is an innate antibacterial mechanism. Cell Host Microbe 12:289

    Google Scholar 

  14. Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7:99–109

    Article  PubMed  CAS  Google Scholar 

  15. Vandenabeele P, Galluzzi L, Vanden BT, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714

    Article  PubMed  CAS  Google Scholar 

  16. Duprez L, Wirawan E, Vanden BT, Vandenabeele P (2009) Major cell death pathways at a glance. Microbes Infect 11:1050–1062

    Article  PubMed  CAS  Google Scholar 

  17. Cohen JJ (1993) Apoptosis. Immunol Today 14:126–130

    Article  PubMed  CAS  Google Scholar 

  18. Fadok VA et al (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216

    PubMed  CAS  Google Scholar 

  19. Fadok VA et al (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90

    Article  PubMed  CAS  Google Scholar 

  20. Henson PM, Tuder RM (2008) Apoptosis in the lung: induction, clearance and detection. Am J Physiol Lung Cell Mol Physiol 294:L601–L611

    Article  PubMed  CAS  Google Scholar 

  21. Krysko DV, D’Herde K, Vandenabeele P (2006) Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 11:1709–1726

    Article  PubMed  Google Scholar 

  22. Duan L, Gan H, Arm J, Remold HG (2001) Cytosolic phospholipase A2 participates with TNF-alpha in the induction of apoptosis of human macrophages infected with Mycobacterium tuberculosis H37Ra. J Immunol 166:7469–7476

    PubMed  CAS  Google Scholar 

  23. Christofferson DE, Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22:263–268

    Article  PubMed  CAS  Google Scholar 

  24. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316

    Article  PubMed  CAS  Google Scholar 

  25. Balcewicz-Sablinska MK, Keane J, Kornfeld H, Remold HG (1998) Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha. J Immunol 161:2636–2641

    PubMed  CAS  Google Scholar 

  26. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629

    Article  PubMed  CAS  Google Scholar 

  27. Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304:463–470

    Article  PubMed  CAS  Google Scholar 

  28. Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164

    Article  PubMed  CAS  Google Scholar 

  29. Bossy-Wetzel E, Newmeyer DD, Green DR (1998) Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17:37–49

    Article  PubMed  CAS  Google Scholar 

  30. Ricci JE et al (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117:773–786

    Article  PubMed  CAS  Google Scholar 

  31. Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J (2008) Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 133:681–692

    Article  PubMed  CAS  Google Scholar 

  32. Baines CP et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662

    Article  PubMed  CAS  Google Scholar 

  33. Gan H et al (2005) Enhancement of antimycobacterial activity of macrophages by stabilization of inner mitochondrial membrane potential. J Infect Dis 191:1292–1300

    Article  PubMed  CAS  Google Scholar 

  34. Connern CP, Halestrap AP (1992) Purification and N-terminal sequencing of peptidyl-prolyl cis-trans isomerase from rat liver mitochondrial matrix reveals the existence of a distinct mitochondrial cyclophilin. Biochem J 284(2):381–385

    PubMed  CAS  Google Scholar 

  35. Maertzdorf J et al (2011) Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun 12:15–22

    Article  PubMed  CAS  Google Scholar 

  36. Abebe M et al (2010) Expression of apoptosis-related genes in an Ethiopian cohort study correlates with tuberculosis clinical status. Eur J Immunol 40:291–301

    Article  PubMed  CAS  Google Scholar 

  37. Herb F et al (2008) ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Hum Mol Genet 17:1052–1060

    Article  PubMed  CAS  Google Scholar 

  38. Tobin DM et al (2010) The lta4 h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717–730

    Article  PubMed  CAS  Google Scholar 

  39. Tobin DM et al (2012) Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148:434–446

    Article  PubMed  CAS  Google Scholar 

  40. Divangahi M, Desjardins D, Nunes-Alves C, Remold HG, Behar SM (2010) Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis. Nat Immunol 11:751–758

    Article  PubMed  CAS  Google Scholar 

  41. Wolf LA, Laster SM (1999) Characterization of arachidonic acid-induced apoptosis. Cell Biochem Biophys 30:353–368

    Article  PubMed  CAS  Google Scholar 

  42. Chang DJ, Ringold GM, Heller RA (1992) Cell killing and induction of manganous superoxide dismutase by tumor necrosis factor-alpha is mediated by lipoxygenase metabolites of arachidonic acid. Biochem Biophys Res Commun 188:538–546

    Article  PubMed  CAS  Google Scholar 

  43. Peterson DA et al (1988) Polyunsaturated fatty acids stimulate superoxide formation in tumor cells: a mechanism for specific cytotoxicity and a model for tumor necrosis factor? Biochem Biophys Res Commun 155:1033–1037

    Article  PubMed  CAS  Google Scholar 

  44. Jayadev S, Linardic CM, Hannun YA (1994) Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor alpha. J Biol Chem 269:5757–5763

    PubMed  CAS  Google Scholar 

  45. Finstad HS et al (1998) Cell proliferation, apoptosis and accumulation of lipid droplets in U937–1 cells incubated with eicosapentaenoic acid. Biochem J 336(2):451–459

    PubMed  CAS  Google Scholar 

  46. Rocca B, FitzGerald GA (2002) Cyclooxygenases and prostaglandins: shaping up the immune response. Int Immunopharmacol 2:603–630

    Article  PubMed  CAS  Google Scholar 

  47. Murakami M et al (2000) Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 275:32783–32792

    Article  PubMed  CAS  Google Scholar 

  48. Sugimoto Y, Narumiya S (2007) Prostaglandin E receptors. J Biol Chem 282:11613–11617

    Article  PubMed  CAS  Google Scholar 

  49. D’Avila H et al (2006) Mycobacterium bovis bacillus Calmette-Guerin induces TLR2-mediated formation of lipid bodies: Intracellular domains for eicosanoid synthesis in vivo. J Immunol 176:3087–3097

    PubMed  Google Scholar 

  50. Almeida PE et al (2009) Mycobacterium bovis bacillus Calmette-Guerin infection induces TLR2-dependent peroxisome proliferator-activated receptor gamma expression and activation: functions in inflammation, lipid metabolism, and pathogenesis. J Immunol 183:1337–1345

    Article  PubMed  CAS  Google Scholar 

  51. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN (2001) Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2:612–619

    Article  PubMed  CAS  Google Scholar 

  52. Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8:349–361

    Article  PubMed  CAS  Google Scholar 

  53. Tobin DM et al (2010) The lta4 h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717–730

    Article  PubMed  CAS  Google Scholar 

  54. Smith J et al (2008) Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infect Immun 76:5478–5487

    Article  PubMed  CAS  Google Scholar 

  55. de Jonge MI et al (2007) (2007) ESAT-6 from Mycobacterium tuberculosis dissociates from its putative chaperone CFP-10 under acidic conditions and exhibits membrane-lysing activity. J Bacteriol 189:6028–6034

    Article  PubMed  Google Scholar 

  56. Roy D et al (2004) A process for controlling intracellular bacterial infections induced by membrane injury. Science 304:1515-1518

    Google Scholar 

  57. Togo T, Alderton JM, Bi GQ, Steinhardt RA (1999) The mechanism of facilitated cell membrane resealing. J Cell Sci 112(5):719–731

    PubMed  CAS  Google Scholar 

  58. Granger BL et al (1990) Characterization and cloning of lgp110, a lysosomal membrane glycoprotein from mouse and rat cells. J Biol Chem 265:12036–12043

    PubMed  CAS  Google Scholar 

  59. Novikoff PM, Tulsiani DR, Touster O, Yam A, Novikoff AB (1983) Immunocytochemical localization of alpha-D-mannosidase II in the Golgi apparatus of rat liver. Proc Natl Acad Sci U S A 80:4364–4368

    Article  PubMed  CAS  Google Scholar 

  60. Martinez I et al (2000) Synaptotagmin VII regulates Ca(2 +)-dependent exocytosis of lysosomes in fibroblasts. J Cell Biol 148:1141–1149

    Article  PubMed  CAS  Google Scholar 

  61. Burgoyne RD, O’Callaghan DW, Hasdemir B, Haynes LP, Tepikin AV (2004) Neuronal Ca2 + -sensor proteins: multitalented regulators of neuronal function. Trends Neurosci 27:203–209

    Article  PubMed  CAS  Google Scholar 

  62. Togo T, Alderton JM, Steinhardt RA (2003) Long-term potentiation of exocytosis and cell membrane repair in fibroblasts. Mol Biol Cell 14:93–106

    Article  PubMed  CAS  Google Scholar 

  63. Regan JW (2003) EP2 and EP4 prostanoid receptor signaling. Life Sci 74:143–153

    Article  PubMed  CAS  Google Scholar 

  64. Bafica A et al (2005) Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J Clin Invest 115:1601–1606

    Article  PubMed  CAS  Google Scholar 

  65. Albert ML (2004) Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol 4:223–231

    Article  PubMed  CAS  Google Scholar 

  66. Yrlid U, Wick MJ (2000) Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med 191:613–624

    Article  PubMed  CAS  Google Scholar 

  67. Schaible UE et al (2003) Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat Med 9:1039–1046

    Article  PubMed  CAS  Google Scholar 

  68. Winau F et al (2006) Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24:105–117

    Article  PubMed  CAS  Google Scholar 

  69. Winau F, Kaufmann SH, Schaible UE (2004) Apoptosis paves the detour path for CD8 T cell activation against intracellular bacteria. Cell Microbiol 6:599–607

    Article  PubMed  CAS  Google Scholar 

  70. Aronoff DM et al (2009) E-prostanoid 3 receptor deletion improves pulmonary host defense and protects mice from death in severe Streptococcus pneumoniae infection. J Immunol 183:2642–2649

    Article  PubMed  CAS  Google Scholar 

  71. Medeiros AI, Serezani CH, Lee SP, Peters-Golden M (2009) Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling. J Exp Med 206:61–68

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

M.D. is supported by the Canadian Institute of Health Research-New Investigator Award. Work in his laboratory is supported by the Canadian Institute of Health Research (CIHR) and The Natural Sciences and Engineering Research Council of Canada (NSERC).

Author information

Authors and Affiliations

  1. Meakins-Christie Laboratories, Department of Microbiology and Immunology, Department of Medicine, McGill University Health Centre, Montreal, QC, H2X 2P2, Canada

    Maziar Divangahi

  2. Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, Canada

    Samuel M. Behar & Heinz Remold

Authors
  1. Maziar Divangahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samuel M. Behar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heinz Remold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Maziar Divangahi , Samuel M. Behar or Heinz Remold .

Editor information

Editors and Affiliations

  1. McGill University, Montreal, H2X 2P2, Québec, Canada

    Maziar Divangahi

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Divangahi, M., Behar, S.M., Remold, H. (2013). Dying to Live: How the Death Modality of the Infected Macrophage Affects Immunity to Tuberculosis. In: Divangahi, M. (eds) The New Paradigm of Immunity to Tuberculosis. Advances in Experimental Medicine and Biology, vol 783. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6111-1_6

Download citation

Publish with us

Policies and ethics

Search

Navigation