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Myeloid-derived suppressor cells control microbial sepsis

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Intensive Care Medicine Aims and scope Submit manuscript

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.

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Abbreviations

AT:

Adoptive transfer

CLP:

Caecal ligation and puncture

GSK:

Glycogen synthase kinase

IL:

Interleukin

LPS:

Lipopolysaccharide

MDSC:

Myeloid-derived suppressor cells

MO-MDSC:

Macrophage-like MDSC

PMN-MDSC:

Neutrophil-like MDSC

ROS:

Reactive oxygen species

TLR:

Toll-like receptor

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

    Article  PubMed  Google Scholar 

  2. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150

    Article  PubMed  CAS  Google Scholar 

  3. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  10. Cripps JG, Gorham JD (2011) MDSC in autoimmunity. Int Immunopharmacol 11:789–793

    Article  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  20. Ford JW, McVicar DW (2009) TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 21:38–46

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  27. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells, linking inflammation and cancer. J Immunol 182:4499–4506

    Article  PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  29. Adib-Conquy M, Cavaillon JM (2009) Compensatory anti-inflammatory response syndrome. Thromb Haemost 101:36–47

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are indebted to Chantal Montemont, Anne-Marie Carpentier and Kevin Patron for technical assistance.

Author information

Authors and Affiliations

  1. Groupe Choc, contrat Avenir INSERM, Faculté de Médecine, Nancy Université, Nancy, France

    Marc Derive, Youcef Bouazza & Sébastien Gibot

  2. EA 4369, Laboratoire de Bactériologie, Faculté de Médecine, Nancy Université, Nancy, France

    Corentine Alauzet

  3. Service de Réanimation Médicale, Hôpital Central, CHU Nancy, 29 boulevard du Maréchal de Lattre de Tassigny, 54035, Nancy Cedex, France

    Sébastien Gibot

Authors
  1. Marc Derive
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  2. Youcef Bouazza
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  3. Corentine Alauzet
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  4. Sébastien Gibot
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Corresponding author

Correspondence to Sébastien Gibot.

Additional information

This article is discussed in the editorial available at: doi:10.1007/s00134-012-2575-3.

Electronic supplementary material

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134_2012_2574_MOESM1_ESM.doc

Supplementary material 1 (DOC 187 kb) LPS-induced gene expression in D3 and D10 MDSCs. Data are representative of three different experiments, normalized by five housekeeping genes and expressed in 2-ΔCt and fold differences of gene expressions between basal and LPS stimulated (100 ng/mL, 6 h) cells. ND non-detectable

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Derive, M., Bouazza, Y., Alauzet, C. et al. Myeloid-derived suppressor cells control microbial sepsis. Intensive Care Med 38, 1040–1049 (2012). https://doi.org/10.1007/s00134-012-2574-4

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  • DOI: https://doi.org/10.1007/s00134-012-2574-4

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