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PMID: 17666571 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo.

Blood ·Vol. 110 ·No. 9 ·2007-11-01 ·Pages 3234-44

Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS

Abstract

Intracellular pathogens and the molecules they express have limited contact with the immune system. Here, we show that macrophages infected with intracellular pathogens Mycobacterium tuberculosis, M bovis BCG, Salmonella typhimurium, or Toxoplasma gondii release from cells small vesicles known as exosomes which contain pathogen-associated molecular patterns (PAMPs). These exosomes, when exposed to uninfected macrophages, stimulate a proinflammatory response in a Toll-like receptor- and myeloid differentiation factor 88-dependent manner. Further, exosomes isolated from the bronchoalveolar lavage fluid (BALF) of M bovis BCG-infected mice contain the mycobacteria components lipoarabinomannan and the 19-kDa lipoprotein and can stimulate TNF-alpha production in naive macrophages. Moreover, exosomes isolated from M bovis BCG- and M tuberculosis-infected macrophages, when injected intranasally into mice, stimulate TNF-alpha and IL-12 production as well as neutrophil and macrophage recruitment in the lung. These studies identify a previously unknown function for exosomes in promoting intercellular communication during an immune response to intracellular pathogens, and we hypothesize that extracellular release of exosomes containing PAMPs is an important mechanism of immune surveillance.

MeSH Terms
Animals Cells, Cultured Inflammation/etiology,pathology Macrophages/metabolism,microbiology,parasitology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mycobacterium bovis/pathogenicity Mycobacterium tuberculosis/pathogenicity Salmonella Infections, Animal/metabolism,pathology Salmonella typhimurium/pathogenicity Secretory Vesicles/metabolism,physiology Toxoplasma/pathogenicity Toxoplasmosis, Animal/metabolism,pathology Tuberculosis/complications,metabolism,pathology,veterinary
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bhatnagar Sanchita
Department of Biological Sciences, Center for Global Health and Infectious Diseases, University of Notre Dame, 130 Galvin Life Science Center, Notre Dame, IN 46556, USA.
Shinagawa Kazuhiko
Castellino Francis J
Schorey Jeffrey S
References (50)
50 references, click to expand
  1. Identification and macrophage-activating activity of glycolipids released from intracellular Mycobacterium bovis BCG.
    Mol Microbiol. 2003 May;48(4):875-88 PMID: 12753183
  2. The Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2.
    Infect Immun. 2003 Aug;71(8):4487-97 PMID: 12874328
  3. Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis.
    Nat Med. 2003 Aug;9(8):1039-46 PMID: 12872166
  4. Exosomes for immunotherapy of cancer.
    Adv Exp Med Biol. 2003;532:215-21 PMID: 12908560
  5. Mycobacterium's arrest of phagosome maturation in macrophages requires Rab5 activity and accessibility to iron.
    Mol Biol Cell. 2003 Aug;14(8):3366-77 PMID: 12925769
  6. Inhibition of HIV-1 infection by a CCR5-binding cyclophilin from Toxoplasma gondii.
    Blood. 2003 Nov 1;102(9):3280-6 PMID: 12855560
  7. Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid.
    Eur Respir J. 2003 Oct;22(4):578-83 PMID: 14582906
  8. Salmonella enterica serovar Typhimurium requires nonsterol precursors of the cholesterol biosynthetic pathway for intracellular proliferation.
    Infect Immun. 2004 Feb;72(2):1036-42 PMID: 14742551
  9. Macrophage surface expression of annexins I and II in the phagocytosis of apoptotic lymphocytes.
    Mol Biol Cell. 2004 Jun;15(6):2863-72 PMID: 15064349
  10. Exosomes for cancer immunotherapy.
    Ann Oncol. 2004;15 Suppl 4:iv141-4 PMID: 15477298
  11. Asymmetric distribution of phospholipids in the membrane of vesicles released during in vitro maturation of guinea pig reticulocytes: evidence precluding a role for "aminophospholipid translocase".
    J Cell Physiol. 1989 Sep;140(3):455-62 PMID: 2777884
  12. Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions.
    Blood. 1989 Oct;74(5):1844-51 PMID: 2790208
  13. B lymphocytes secrete antigen-presenting vesicles.
    J Exp Med. 1996 Mar 1;183(3):1161-72 PMID: 8642258
  14. Aggregation reroutes molecules from a recycling to a vesicle-mediated secretion pathway during reticulocyte maturation.
    J Cell Sci. 1997 Aug;110 ( Pt 16):1867-77 PMID: 9296387
  15. A role for POR1, a Rac1-interacting protein, in ARF6-mediated cytoskeletal rearrangements.
    EMBO J. 1997 Sep 1;16(17):5445-54 PMID: 9312003
  16. Intracellular fate of vacuoles containing Toxoplasma gondii is determined at the time of formation and depends on the mechanism of entry.
    J Immunol. 1997 Nov 1;159(9):4452-9 PMID: 9379044
  17. Macrophages resistant to endogenously generated nitric oxide-mediated apoptosis are hypersensitive to exogenously added nitric oxide donors: dichotomous apoptotic response independent of caspase 3 and reversal by the mitogen-activated protein kinase kinase (MEK) inhibitor PD 098059.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5045-50 PMID: 9560225
  18. The nuclear envelope serves as an intermediary between the ER and Golgi complex in the intracellular parasite Toxoplasma gondii.
    J Cell Sci. 1999 Aug;112 ( Pt 16):2631-8 PMID: 10413671
  19. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells.
    Blood. 2004 Nov 15;104(10):3257-66 PMID: 15284116
  20. TLR11 activation of dendritic cells by a protozoan profilin-like protein.
    Science. 2005 Jun 10;308(5728):1626-9 PMID: 15860593
  21. Mechanisms of group B streptococcal-induced apoptosis of murine macrophages.
    J Immunol. 2005 Aug 15;175(4):2555-62 PMID: 16081829
  22. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses.
    Blood Cells Mol Dis. 2005 Sep-Oct;35(2):89-93 PMID: 15990342
  23. The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis.
    J Exp Med. 2005 Oct 3;202(7):987-99 PMID: 16203868
  24. Contribution of host lipids to Toxoplasma pathogenesis.
    Cell Microbiol. 2006 Jan;8(1):1-9 PMID: 16367861
  25. Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis.
    Immunity. 2006 Jan;24(1):105-17 PMID: 16413927
  26. Role of exosomes in immune regulation.
    J Cell Mol Med. 2006 Apr-Jun;10(2):364-75 PMID: 16796805
  27. Prospects for exosomes in immunotherapy of cancer.
    J Cell Mol Med. 2006 Apr-Jun;10(2):376-88 PMID: 16796806
  28. Exosomes: a common pathway for a specialized function.
    J Biochem. 2006 Jul;140(1):13-21 PMID: 16877764
  29. Dendritic cell derived-exosomes: biology and clinical implementations.
    J Leukoc Biol. 2006 Sep;80(3):471-8 PMID: 16809645
  30. Exosomes: from biogenesis and secretion to biological function.
    Immunol Lett. 2006 Nov 15;107(2):102-8 PMID: 17067686
  31. Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation.
    Neuron. 2006 Dec 21;52(6):1061-72 PMID: 17178408
  32. Contribution of Toll-like receptors to the innate immune response to Gram-negative and Gram-positive bacteria.
    Blood. 2007 Feb 15;109(4):1574-83 PMID: 17038528
  33. The high-affinity IgE receptor (FcepsilonRI) blocks apoptosis in normal human monocytes.
    J Clin Invest. 2000 Jan;105(2):183-90 PMID: 10642596
  34. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device.
    J Cell Sci. 2000 Oct;113 Pt 19:3365-74 PMID: 10984428
  35. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry.
    J Immunol Methods. 2001 Jan 1;247(1-2):163-74 PMID: 11150547
  36. Mycobacterial surface moieties are released from infected macrophages by a constitutive exocytic event.
    Eur J Cell Biol. 2001 Jan;80(1):31-40 PMID: 11211933
  37. Trafficking and release of mycobacterial lipids from infected macrophages.
    Traffic. 2000 Mar;1(3):235-47 PMID: 11208107
  38. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming.
    Nat Med. 2001 Mar;7(3):297-303 PMID: 11231627
  39. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles.
    J Immunol. 2001 Jun 15;166(12):7309-18 PMID: 11390481
  40. Different Toll-like receptor agonists induce distinct macrophage responses.
    J Leukoc Biol. 2001 Jun;69(6):1036-44 PMID: 11404392
  41. Toll-like receptors control activation of adaptive immune responses.
    Nat Immunol. 2001 Oct;2(10):947-50 PMID: 11547333
  42. Role of complement in Mycobacterium avium pathogenesis: in vivo and in vitro analyses of the host response to infection in the absence of complement component C3.
    Infect Immun. 2001 Dec;69(12):7729-35 PMID: 11705954
  43. Toll-like receptors and innate immunity.
    Nat Rev Immunol. 2001 Nov;1(2):135-45 PMID: 11905821
  44. Sorting out signals in fly endosomes.
    Traffic. 2002 Feb;3(2):87-91 PMID: 11929598
  45. Differential regulation of the mitogen-activated protein kinases by pathogenic and nonpathogenic mycobacteria.
    Infect Immun. 2002 Jun;70(6):3040-52 PMID: 12010996
  46. The exosome pathway in K562 cells is regulated by Rab11.
    J Cell Sci. 2002 Jun 15;115(Pt 12):2505-15 PMID: 12045221
  47. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins.
    J Immunol. 2002 Jul 1;169(1):10-4 PMID: 12077222
  48. Exosomes: composition, biogenesis and function.
    Nat Rev Immunol. 2002 Aug;2(8):569-79 PMID: 12154376
  49. Exosomes: novel organelles implicated in immunomodulation and apoptosis.
    Yale J Biol Med. 2002 Mar-Apr;75(2):95-101 PMID: 12230314
  50. Toll-like receptors and their ligands.
    Curr Top Microbiol Immunol. 2002;270:81-92 PMID: 12467245
Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2007-03-079152
Published
2007-11-01
Epub
2007-00-31
Pages
3234-44
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2200902
Subset
IM
Grants
NIAID NIH HHS · HHSN266200400091C · United States
NIAID NIH HHS · AI 056979 · United States
NHLBI NIH HHS · P01 HL073750 · United States
NIAID NIH HHS · R01 AI056979 · United States
NIAID NIH HHS · R01 AI052439 · United States
NHLBI NIH HHS · HL 073750 · United States
NIAID NIH HHS · AI 052439 · United States
External Links
PubMed source DOI: 10.1182/blood-2007-03-079152 PMC Full Text View journal details
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