Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Emerging role of extracellular vesicles in inflammatory diseases

Nature Reviews Rheumatology volume 10, pages 356–364 (2014)Cite this article

Subjects

Key Points

  • The evolutionarily conserved release of extracellular vesicles (EVs), including exosomes, microvesicles (microparticles) and apoptotic vesicles, is a previously unappreciated type of secretion by cells

  • EVs trigger inflammation by carrying pathogen-associated and damage-associated molecular patterns or pathogenic autoantigens

  • EV-associated cytokines, lipid mediators and microRNAs contribute to the propagation phase of inflammatory diseases

  • EVs contain proteases and glycosidases that could contribute to tissue destruction

  • EVs could be used as novel therapeutic vehicles, immunomodulators and therapeutic targets

Abstract

The discovery that submicron-sized extracellular vesicles (EVs) are generated by both prokaryotic and eukaryotic cells might have a profound effect on experimental and clinical sciences, and could pave the way for new strategies to combat various diseases. EVs are carriers of pathogen-associated and damage-associated molecular patterns, cytokines, autoantigens and tissue-degrading enzymes. In addition to a possible role in the pathogenesis of a number of inflammatory conditions, such as infections and autoimmune diseases, EVs, including microvesicles (also known as microparticles), exosomes and apoptotic vesicles, have therapeutic potential and might be used as biomarkers for inflammatory diseases. Therefore, molecular diagnostics and targeted therapy could benefit from expanding knowledge in the field. In this Review, we summarize important developments and propose that extracellular vesicles could be used as therapeutic vehicles and as targets for the treatment and prevention of inflammatory diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Biological samples contain multiple types of extracellular vesicles.
Figure 2: Extracellular vesicles contribute to inflammation.
Figure 3: Extracellular vesicles in the inflamed joint.

Similar content being viewed by others

References

  1. Théry, C., Ostrowski, M. & Segura, E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9, 581–593 (2009).

    Article  PubMed  CAS  Google Scholar 

  2. György, B. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell. Mol. Life Sci. 68, 2667–2688 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. van der Pol., E., Böing, A. N., Harrison, P., Sturk, A. & Nieuwland, R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 64, 676–705 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Akers, J. C., Gonda, D., Kim, R., Carter, B. S. & Chen, C. C. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J. Neurooncol. 113, 1–11 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Morello, M. et al. Large oncosomes mediate intercellular transfer of functional microRNA. Cell Cycle 12, 3526–3536 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Witwer, K. W. et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2, 20360 (2013).

    Article  CAS  Google Scholar 

  7. Muralidharan-Chari, V., Clancy, J. W., Sedgwick, A. & D' Souza-Schorey, C. Microvesicles: mediators of extracellular communication during cancer progression. J. Cell Sci. 123, 1603–1611 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nolte-'t Hoen, E. N., Quantitative and qualitative flow cytometric analysis of nanosized cell-derived membrane vesicles. Nanomedicine 8, 712–720 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. van der Pol., E., van Gemert, M. J., Sturk, A., Nieuwland, R. & van Leeuwen, T. G. Single vs. swarm detection of microparticles and exosomes by flow cytometry. J. Thromb. Haemost. 10, 919–930 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Lacroix, R., Robert, S., Poncelet, P., Kasthuri, R. S., Key, N. S. & Dignat-George, F. Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J. Thromb. Haemost. 8, 2571–2574 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Johnstone, R. M., Adam, M., Hammond, J. R., Orr, L. & Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 262, 9412–9420 (1987).

    CAS  PubMed  Google Scholar 

  12. Verweij, F. J. et al. LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-κB activation. EMBO J. 30, 2115–2129 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell. Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Pilzer, D., Gasser, O., Moskovich, O., Schifferli, J. A. & Fishelson, Z. Emission of membrane vesicles: roles in complement resistance, immunity and cancer. Springer Semin. Immunopathol. 27, 375–387 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Regev-Rudzki, N. et al. Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. Cell. 153, 1120–1133 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Timar, C. I. et al. Antibacterial effect of microvesicles released from human neutrophilic granulocytes. Blood 121, 510–518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Goh, F. G. & Midwood, K. S. Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology (Oxford) 51, 7–23, (2012).

    Article  CAS  Google Scholar 

  18. Deatherage, B. L. & Cookson, B. T. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect. Immun. 80, 1948–1957 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nakao, R. et al. Outer membrane vesicles of Porphyromonas gingivalis elicit a mucosal immune response. PLoS ONE 6, e26163 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaparakis, M. et al. Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell. Microbiol. 12, 372–385 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Hong, S. W. et al. Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation. Allergy 66, 351–359 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Kim, M. R. et al. Staphylococcus aureus-derived extracellular vesicles induce neutrophilic pulmonary inflammation via both TH1 and TH17 cell responses. Allergy 67, 1271–1281 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Prados-Rosales, R. et al. Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J. Clin. Invest. 121, 1471–1483 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Gehrmann, U. et al. Nanovesicles from Malassezia sympodialis and host exosomes induce cytokine responses--novel mechanisms for host-microbe interactions in atopic eczema. PLoS ONE 6, e21480 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schiller, M. et al. During apoptosis HMGB1 is translocated into apoptotic cell-derived membraneous vesicles. Autoimmunity 46, 342–346 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Ayna, G. et al. ATP release from dying autophagic cells and their phagocytosis are crucial for inflammasome activation in macrophages. PLoS ONE 7, e40069, (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Turiak, L. et al. Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice. J. Proteomics 74, 2025–2033 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Cloutier, N. et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol. Med. 5, 235–249 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Skriner, K., Adolph, K., Jungblut, P. R. & Burmester, G. R. Association of citrullinated proteins with synovial exosomes. Arthritis Rheum. 54, 3809–3814 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Nielsen, C. T. et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum. 64, 1227–1236 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Pisetsky, D. S. Microparticles as autoantigens: making immune complexes big. Arthritis Rheum. 64, 958–961 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ullal, A. J. et al. Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus. J. Autoimmun. 36, 173–180 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Ullal, A. J. & Pisetsky, D. S. The role of microparticles in the generation of immune complexes in murine lupus. Clin. Immunol. 146, 1–9 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Kapsogeorgou, E. K., Abu-Helu, R. F., Moutsopoulos, H. M. & Manoussakis, M. N. Salivary gland epithelial cell exosomes: a source of autoantigenic ribonucleoproteins. Arthritis Rheum. 52, 1517–1521 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Mor-Vaknin, N. et al. DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. Arthritis Rheum. 63, 556–567 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Silva, M. T. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett. 584, 4491–4499 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Lamkanfi, M. Emerging inflammasome effector mechanisms. Nat. Rev. Immunol. 11, 213–220 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Sheng, H. et al. Insulinoma-released exosomes or microparticles are immunostimulatory and can activate autoreactive T cells spontaneously developed in nonobese diabetic mice. J. Immunol. 187, 1591–1600 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Rahman, M. J., Regn, D., Bashratyan, R. & Dai, Y. D. Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes. http://dx.doi:10.2337/db13-0859.

    Article  PubMed  CAS  Google Scholar 

  40. Kojima, F., Kapoor, M., Kawai, S. & Crofford, L. J. New insights into eicosanoid biosynthetic pathways: implications for arthritis. Expert Rev. Clin. Immunol. 2, 277–291 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Barry, O. P., Pratico, D., Lawson, J. A. & FitzGerald, G. A. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J. Clin. Invest. 99, 2118–2127 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Esser, J. et al. Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration. J. Allergy Clin. Immunol. 126, 1032–1040 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Gulinelli, S. et al. IL-18 associates to microvesicles shed from human macrophages by a LPS/TLR-4 independent mechanism in response to P2X receptor stimulation. Eur. J. Immunol. 42, 3334–3345 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Nickel, W. & Rabouille, C. Mechanisms of regulated unconventional protein secretion. Nat. Rev. Mol. Cell Biol. 10, 148–155 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Pizzirani, C. et al. Stimulation of P2 receptors causes release of IL-1β-loaded microvesicles from human dendritic cells. Blood 109, 3856–3864 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Boilard, E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327, 580–583 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Baj-Krzyworzeka, M. et al. Tumour-derived microvesicles contain interleukin-8 and modulate production of chemokines by human monocytes. Anticancer Res. 31, 1329–1335 (2011).

    CAS  PubMed  Google Scholar 

  48. Truman, L. A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Fabbri, M. TLRs as miRNA receptors. Cancer Res. 72, 6333–6337 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Ohshima, K. et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS ONE 5, e13247 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Lehmann, S. M. et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat. Neurosci. 15, 827–835 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Fabbri, M. et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl Acad. Sci. USA 109, E2110–E2116 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fabbri, M., Paone, A., Calore, F., Galli, R. & Croce, C. M. A new role for microRNAs, as ligands of Toll-like receptors. RNA Biol. 10, 169–174 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Laffont, B. et al. Activated platelets can deliver mRNA regulatory Ago2–microRNA complexes to endothelial cells via microparticles. Blood 122, 253–261 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Lo Cicero, A., Majkowska, I., Nagase, H., Di Liegro, I. & Troeberg, L. Microvesicles shed by oligodendroglioma cells and rheumatoid synovial fibroblasts contain aggrecanase activity. Matrix Biol. 31, 229–233 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Shimoda, M. & Khokha, R. Proteolytic factors in exosomes. Proteomics 13, 1624–1636 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Li, C. J. et al. Novel proteolytic microvesicles released from human macrophages after exposure to tobacco smoke. Am. J. Pathol. 182, 1552–1562 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ortutay, Z. et al. Synovial fluid exoglycosidases are predictors of rheumatoid arthritis and are effective in cartilage glycosaminoglycan depletion. Arthritis Rheum. 48, 2163–2172 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Pasztoi, M. et al. Gene expression and activity of cartilage degrading glycosidases in human rheumatoid arthritis and osteoarthritis synovial fibroblasts. Arthritis Res. Ther. 11, R68 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Pasztoi, M. et al. The recently identified hexosaminidase D enzyme substantially contributes to the elevated hexosaminidase activity in rheumatoid arthritis. Immunol. Lett. 149, 71–76 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Knijff-Dutmer, E. A., Koerts, J., Nieuwland, R., Kalsbeek-Batenburg, E. M. & van de Laar, M. A. Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthritis Rheum. 46, 1498–1503 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Berckmans, R. J. et al. Cell-derived microparticles in synovial fluid from inflamed arthritic joints support coagulation exclusively via a factor VII-dependent mechanism. Arthritis Rheum. 46, 2857–2866 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Sellam, J. et al. Increased levels of circulating microparticles in primary Sjogren's syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity. Arthritis Res. Ther. 11, R156 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. György, B. et al. Improved flow cytometric assessment reveals distinct microvesicle (cell-derived microparticle) signatures in joint diseases. PLoS ONE 7, e49726 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Wang, H. et al. Oxidized low-density lipoprotein-dependent platelet-derived microvesicles trigger procoagulant effects and amplify oxidative stress. Mol. Med. 18, 159–166 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Rautou, P. E. et al. Microparticles, vascular function, and atherothrombosis. Circ. Res. 109, 593–606 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Messer, L. et al. Microparticle-induced release of B-lymphocyte regulators by rheumatoid synoviocytes. Arthritis Res. Ther. 11, R40 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Berckmans, R. J. et al. Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Arthritis Res. Ther. 7, R536–544 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gyorgy, B. et al. Detection and isolation of cell-derived microparticles are compromised by protein complexes due to shared biophysical parameters. Blood 117, e39–e48 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Jungel, A. et al. Microparticles stimulate the synthesis of prostaglandin E(2) via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1. Arthritis Rheum. 56, 3564–3574 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Distler, J. H. et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. Proc. Natl Acad. Sci. USA 102, 2892–2897 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Reich, N. et al. Microparticles stimulate angiogenesis by inducing ELR(+) CXC-chemokines in synovial fibroblasts. J. Cell. Mol. Med. 15, 756–762 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Pereira, J. et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb. Haemost. 95, 94–99 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Ostergaard, O. et al. Unique protein signature of circulating microparticles in systemic lupus erythematosus. Arthritis Rheum. http://dx.doi.org/10.1002/art.38065.

  75. Pisetsky, D. S., Gauley, J. & Ullal, A. J. Microparticles as a source of extracellular DNA. Immunol. Res. 49, 227–234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Parker, B. et al. Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-203028.

  77. Guiducci, S. et al. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis. Arthritis Rheum. 58, 2845–2853 (2008).

    Article  PubMed  Google Scholar 

  78. Sgonc, R. et al. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J. Clin. Invest. 98, 785–792 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Aharon, A., Tamari, T. & Brenner, B. Monocyte derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells. Thromb. Haemost. 100, 878–885 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Cloutier, N. et al. Platelets can enhance vascular permeability. Blood 120, 1334–1343 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Sun, D. et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18, 1606–1614 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kooijmans, S. A. et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J. Control Release 172, 229–238 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Bolukbasi, M. F. et al. miR-1289 and “Zipcode”-like sequence enrich mRNAs in microvesicles. Mol. Ther. Nucleic. Acids. 1, e10 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Shen, B., Wu, N., Yang, J. M. & Gould, S. J. Protein targeting to exosomes/microvesicles by plasma membrane anchors. J. Biol. Chem. 286, 14383–14395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Maguire, C. A. et al. Microvesicle-associated AAV vector as a novel gene delivery system. Mol. Ther. 20, 960–971 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wahlgren, J. et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 40, e130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ohno, S. et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21, 185–191 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Akao, Y. et al. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol. Ther. 19, 395–399 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Zhuang, X. et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol. Ther. 19, 1769–1779 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang, G. J. et al. Thymus exosomes-like particles induce regulatory T cells. J. Immunol. 181, 5242–5248 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Yang, X., Meng, S., Jiang, H., Chen, T. & Wu, W. Exosomes derived from interleukin-10-treated dendritic cells can inhibit trinitrobenzene sulfonic acid-induced rat colitis. Scand. J. Gastroenterol. 45, 1168–1177 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Kim, S. H. et al. Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J. Immunol. 174, 6440–6448 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Ruffner, M. A. et al. B7–1/2, but not PD-L1/2 molecules, are required on IL-10-treated tolerogenic DC and DC-derived exosomes for in vivo function. Eur. J. Immunol. 39, 3084–3090 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kim, S. H., Bianco, N. R., Shufesky, W. J., Morelli, A. E. & Robbins, P. D. MHC class II+ exosomes in plasma suppress inflammation in an antigen-specific and Fas ligand/Fas-dependent manner. J. Immunol. 179, 2235–2241 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Cai, Z. et al. Immunosuppressive exosomes from TGF-beta1 gene-modified dendritic cells attenuate Th17-mediated inflammatory autoimmune disease by inducing regulatory T cells. Cell Res. 22, 607–610 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Kim, S. H., Bianco, N. R., Shufesky, W. J., Morelli, A. E. & Robbins, P. D. Effectivetreatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4. J. Immunol. 179, 2242–2249 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Kim, S. H. et al. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol. Ther. 13, 289–300 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Bianco, N. R., Kim, S. H., Ruffner, M. A. & Robbins, P. D. Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models. Arthritis Rheum. 60, 380–389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang, J. et al. Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma. Biochem. Biophys. Res. Commun. 366, 579–584 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Meijer, H., Reinecke, J., Becker, C., Tholen, G. & Wehling, P. The production of anti-inflammatory cytokines in whole blood by physico-chemical induction. Inflamm. Res. 52, 404–407 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Kelly, R. W. et al. Extracellular organelles (prostasomes) are immunosuppressive components of human semen. Clin. Exp. Immunol. 86, 550–556 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shen, Y. et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12, 509–520 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Savina, A., Furlan, M., Vidal, M. & Colombo, M. I. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J. Biol. Chem. 278, 20083–20090 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Thompson, C. A., Purushothaman, A., Ramani, V. C., Vlodavsky, I. & Sanderson, R. D. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J. Biol. Chem. 288, 10093–10099 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Blanchard, N. et al. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J. Immunol. 168, 3235–3241 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Qu, Y. et al. P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1. J. Immunol. 182, 5052–5062 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Constantinescu, P. et al. P2X7 receptor activation induces cell death and microparticle release in murine erythroleukemia cells. Biochim. Biophys. Acta 1798, 1797–1804 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Crespin, M., Vidal, C., Picard, F., Lacombe, C. & Fontenay, M. Activation of PAK1/2 during the shedding of platelet microvesicles. Blood Coagul. Fibrinolysis 20, 63–70 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Parolini, I. et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 284, 34211–34222 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Smith, S. K. et al. Mechanisms by which intracellular calcium induces susceptibility to secretory phospholipase A2 in human erythrocytes. J. Biol. Chem. 276, 22732–22741 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Barteneva, N. S. et al. Circulating microparticles: square the circle. BMC Cell Biol. 14, 23 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ostrowski, M. et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19–30 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Muralidharan-Chari, V. et al. ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr. Biol. 19, 1875–1885 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Crescitelli, R. et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J. Extracellul. Vesicles, 2, 20677 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by OTKA NK 84,043 (E.I.B.) and K77537 (G.N.), and FP7-PEOPLE-2011-ITN-PITN-GA-2011-289,033 “DYNANO” (E.I.B.). This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TÁMOP 4.2.4. A/-11-1-2012-0001 'National Excellence Program' (B.G.).

Author information

Authors and Affiliations

  1. Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary

    Edit I. Buzas, Bence György & András Falus

  2. Department of Rheumatology, Polyclinic of the Hospitaller Brothers of St John of God, Frankel Leó út 54, Budapest, H-1023, Hungary

    György Nagy

  3. Centre for Experimental Rheumatology, Clinic of Rheumatology, University Hospital, Gloriastrasse 25, Zürich, CH-8091, Switzerland

    Steffen Gay

Authors
  1. Edit I. Buzas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bence György
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. György Nagy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. András Falus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steffen Gay
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.I.B. and B.G. researched the data for the article, substantially contributed to discussion of the article and wrote the article. E.I.B., G.N., A.F. and S.G. contributed to reviewing and editing of the manuscript before submission.

Corresponding author

Correspondence to Edit I. Buzas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buzas, E., György, B., Nagy, G. et al. Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol 10, 356–364 (2014). https://doi.org/10.1038/nrrheum.2014.19

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2014.19

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing