Log in | Register

Myeloid-derived suppressor cells control microbial sepsis

Marc Derive| Youcef Bouazza| Corentine Alauzet| Sébastien Gibot
Experimental
Volume 38, Issue 6 / June , 2012

Pages 1040 - 1049

Abstract

Purpose

To investigate the role of myeloid-derived suppressor cells (MDSCs) during sepsis in mice. MDSCs are a heterogeneous population of cells that expand during cancer, inflammation and infection. These cells, by their ability to suppress T lymphocyte proliferation, regulate immune responses during various diseases. Their role during microbial infections is scarcely known.

Methods

Septic shock was induced by caecal ligation and puncture in adult male BALB/c mice; sham-operated animals served as controls. Animals were killed under anaesthesia to harvest blood and organs.

Results

Polymicrobial sepsis induced a progressive accumulation of MDSCs in spleens that were found to be enlarged in surviving mice. MDSCs harvested at day 10 after the onset of infection were highly responsive to LPS in terms of cytokines secretion, NF-kB activation, ROS production and arginase I activity, whereas early-appearing (day 3) MDSCs poorly responded to this stimulus. By contrast, both day 3 and day 10 MDSCs were able to inhibit T cell proliferation. Adoptive transfer of day 10 MDSCs to septic mice attenuated peritoneal cytokine production, increased bacterial clearance and dramatically improved survival rate.

Conclusion

These results provide new information on the role of MDSCs, suggesting a protective effect during sepsis. Pharmacologic agents known to promote the expansion of MDSCs should thus be further studied for sepsis treatment.

Keywords

References

  1. Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554
    • View reference on PubMed
    • View reference on publisher's website
  2. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150
    • View reference on PubMed
    • View reference on publisher's website
  3. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174
    • View reference on PubMed
    • View reference on publisher's website
  4. Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA (2008) Identification of discrete tumor‐induced myeloid‐derived suppressor cell subpopulations with distinct T cell‐suppressive activity. Blood 111:4233–4244
    • View reference on PubMed
    • View reference on publisher's website
  5. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid‐derived suppressor cells in tumor‐bearing mice. J Immunol 181:5791–5802
    • View reference on PubMed
  6. Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244
    • View reference on PubMed
    • View reference on publisher's website
  7. Munera V, Popovic PJ, Bryk J, Pribis J, Caba D, Matta BM, Zenati M, Ochoa JB (2010) Stat-6 dependent induction of myeloid-derived suppressor cells after physical injury regulates nitric oxide response to endotoxin. Ann Surg 251:120–126
    • View reference on PubMed
    • View reference on publisher's website
  8. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176:284–290
    • View reference on PubMed
  9. Noel G, Wang Q, Schwemberger S, Hanson C, Giacalone N, Haar L, Ogle CK (2011) Neutrophils, not monocyte/macrophages, are the major splenic source of postburn IL-10. Shock 36:149–155
    • View reference on PubMed
    • View reference on publisher's website
  10. Cripps JG, Gorham JD (2011) MDSC in autoimmunity. Int Immunopharmacol 11:789–793
    • View reference on publisher's website
  11. Goni O, Alcaide P, Fresno M (2002) Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1(+))CD11b(+)immature myeloid suppressor cells. I. Int Immunol 14:1125–1134
    • View reference on PubMed
    • View reference on publisher's website
  12. Voisin MB, Buzoni-Gatel D, Bout D, Velge-Roussel F (2004) Both expansion of regulatory GR1 + CD11b + myeloid cells and anergy of T lymphocytes participate in hyporesponsiveness of the lung-associated immune system during acute toxoplasmosis. Infect Immun 72:5487–5492
    • View reference on PubMed
    • View reference on publisher's website
  13. Cuervo H, Guerrero NA, Carbajosa S, Beschin A, De Baetselier P, Girones N, Fresno M (2011) Myeloid-derived suppressor cells infiltrate the heart in acute Trypanosoma cruzi infection. J Immunol 187:2656–2665
    • View reference on PubMed
    • View reference on publisher's website
  14. Pereira WF, Ribeiro-Gomes FL, Guillermo LV, Vellozo NS, Montalvao F, Dosreis GA, Lopes MF (2011) Myeloid-derived suppressor cells help protective immunity to Leishmania major infection despite suppressed T cell responses. J Leuk Biol 90:1191–1197
    • View reference on publisher's website
  15. Chen S, Akbar SM, Abe M, Hiasa Y, Onji M (2011) Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus. Clin Exp Immunol 166:134–142
    • View reference on PubMed
    • View reference on publisher's website
  16. Tacke R, Lee HC, Goh C, Courtney J, Polyak SJ, Rosen HR, Hahn YS (2011) Myeloid suppressor cells induced by hepatitis C virus suppress T cell responses through the production of reactive oxygen species. Hepatology. doi:10.1002/hep.24700
  17. Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O’Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL (2007) MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 204:1463–1474
    • View reference on PubMed
    • View reference on publisher's website
  18. Cuenca AG, Delano MJ, Kelly-Scumpia KM, Moreno C, Scumpia PO, Laface DM, Heyworth PG, Efron PA, Moldawer LL (2011) A paradoxical role for myeloid derived suppressor cells in sepsis and trauma. Mol Med 17:281–292
    • View reference on PubMed
    • View reference on publisher's website
  19. Gibot S, Kolopp-Sarda MN, Béné MC, Bollaert PE, Lozniewski A, Mory F, Levy B, Faure GC (2004) A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis. J Exp Med 200:1419–1426
    • View reference on PubMed
    • View reference on publisher's website
  20. Ford JW, McVicar DW (2009) TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 21:38–46
    • View reference on PubMed
    • View reference on publisher's website
  21. Youn JI, Gabrilovich DI (2010) The biology of myeloid-derived suppressor cells, the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 40:2969–2975
    • View reference on PubMed
    • View reference on publisher's website
  22. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2007) Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 67:10019–10026
    • View reference on PubMed
    • View reference on publisher's website
  23. Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Müller M, Blander JM, Tacke F, Trautwein C (2010) Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med 207:1453–1464
    • View reference on PubMed
    • View reference on publisher's website
  24. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rébé C, Ghiringhelli F (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471
    • View reference on PubMed
  25. Yoshimura A, Ohishi HM, Aki D, Hanada T (2004) Regulation of TLR signaling and inflammation by SOCS family proteins. J Leuk Biol 75:422–427
    • View reference on publisher's website
  26. Wang H, Brown J, Martin M (2011) Glycogen synthase kinase 3: a point of convergence for the host inflammatory response. Cytokine 53:130–140
    • View reference on PubMed
    • View reference on publisher's website
  27. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells, linking inflammation and cancer. J Immunol 182:4499–4506
    • View reference on PubMed
    • View reference on publisher's website
  28. Makarenkova VP, Bansal V, Matta BM, Perez LA, Ochoa JB (2006) CD11b +/Gr-1 + myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol 176:2085–2094
    • View reference on PubMed
  29. Adib-Conquy M, Cavaillon JM (2009) Compensatory anti-inflammatory response syndrome. Thromb Haemost 101:36–47
    • View reference on PubMed
  30. Noel G, Wang Q, Osterburg A, Schwemberger S, James L, Haar L, Giacalone N, Thomas I, Ogle C (2010) A ribonucleotide reductase inhibitor reverses burn-induced inflammatory defects. Shock 34:535–544
    • View reference on PubMed
    • View reference on publisher's website
  31. Delano MJ, Thayer T, Gabrilovich S, Kelly-Scumpia KM, Winfield RD, Scumpia PO, Cuenca AG, Warner E, Wallet SM, Wallet MA, O’Malley KA, Ramphal R, Clare-Salzer M, Efron PA, Mathews CE, Moldawer LL (2011) Sepsis induces early alterations in innate immunity that impact mortality to secondary infection. J Immunol 186:195–202
    • View reference on PubMed
    • View reference on publisher's website

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement