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Published in: Intensive Care Medicine 6/2012

01-06-2012 | Experimental

Myeloid-derived suppressor cells control microbial sepsis

Authors: Marc Derive, Youcef Bouazza, Corentine Alauzet, Sébastien Gibot

Published in: Intensive Care Medicine | Issue 6/2012

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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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Literature
1.
go back to reference 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 348:1546–1554PubMedCrossRef 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 348:1546–1554PubMedCrossRef
2.
go back to reference Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150PubMedCrossRef Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150PubMedCrossRef
3.
go back to reference Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174PubMedCrossRef Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174PubMedCrossRef
4.
go back to reference 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 111:4233–4244PubMedCrossRef 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 111:4233–4244PubMedCrossRef
5.
go back to reference Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid‐derived suppressor cells in tumor‐bearing mice. J Immunol 181:5791–5802PubMed Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid‐derived suppressor cells in tumor‐bearing mice. J Immunol 181:5791–5802PubMed
6.
go back to reference 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 22:238–244PubMedCrossRef 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 22:238–244PubMedCrossRef
7.
go back to reference 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 251:120–126PubMedCrossRef 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 251:120–126PubMedCrossRef
8.
go back to reference Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176:284–290PubMed Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176:284–290PubMed
9.
go back to reference 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 36:149–155PubMedCrossRef 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 36:149–155PubMedCrossRef
10.
go back to reference Cripps JG, Gorham JD (2011) MDSC in autoimmunity. Int Immunopharmacol 11:789–793CrossRef Cripps JG, Gorham JD (2011) MDSC in autoimmunity. Int Immunopharmacol 11:789–793CrossRef
11.
go back to reference 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 14:1125–1134PubMedCrossRef 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 14:1125–1134PubMedCrossRef
12.
go back to reference 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 72:5487–5492PubMedCrossRef 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 72:5487–5492PubMedCrossRef
13.
go back to reference 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 187:2656–2665PubMedCrossRef 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 187:2656–2665PubMedCrossRef
14.
go back to reference 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 90:1191–1197CrossRef 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 90:1191–1197CrossRef
15.
go back to reference 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 166:134–142PubMedCrossRef 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 166:134–142PubMedCrossRef
16.
go back to reference 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 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.
go back to reference 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 204:1463–1474PubMedCrossRef 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 204:1463–1474PubMedCrossRef
18.
go back to reference 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 17:281–292PubMedCrossRef 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 17:281–292PubMedCrossRef
19.
go back to reference 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 200:1419–1426PubMedCrossRef 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 200:1419–1426PubMedCrossRef
20.
go back to reference Ford JW, McVicar DW (2009) TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 21:38–46PubMedCrossRef Ford JW, McVicar DW (2009) TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 21:38–46PubMedCrossRef
21.
go back to reference 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 40:2969–2975PubMedCrossRef 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 40:2969–2975PubMedCrossRef
22.
go back to reference 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 67:10019–10026PubMedCrossRef 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 67:10019–10026PubMedCrossRef
23.
go back to reference 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 207:1453–1464PubMedCrossRef 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 207:1453–1464PubMedCrossRef
24.
go back to reference 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 120:457–471PubMed 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 120:457–471PubMed
25.
go back to reference Yoshimura A, Ohishi HM, Aki D, Hanada T (2004) Regulation of TLR signaling and inflammation by SOCS family proteins. J Leuk Biol 75:422–427CrossRef Yoshimura A, Ohishi HM, Aki D, Hanada T (2004) Regulation of TLR signaling and inflammation by SOCS family proteins. J Leuk Biol 75:422–427CrossRef
26.
go back to reference Wang H, Brown J, Martin M (2011) Glycogen synthase kinase 3: a point of convergence for the host inflammatory response. Cytokine 53:130–140PubMedCrossRef Wang H, Brown J, Martin M (2011) Glycogen synthase kinase 3: a point of convergence for the host inflammatory response. Cytokine 53:130–140PubMedCrossRef
27.
go back to reference Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells, linking inflammation and cancer. J Immunol 182:4499–4506PubMedCrossRef Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells, linking inflammation and cancer. J Immunol 182:4499–4506PubMedCrossRef
28.
go back to reference 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 176:2085–2094PubMed 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 176:2085–2094PubMed
29.
go back to reference Adib-Conquy M, Cavaillon JM (2009) Compensatory anti-inflammatory response syndrome. Thromb Haemost 101:36–47PubMed Adib-Conquy M, Cavaillon JM (2009) Compensatory anti-inflammatory response syndrome. Thromb Haemost 101:36–47PubMed
30.
go back to reference 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 34:535–544PubMedCrossRef 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 34:535–544PubMedCrossRef
31.
go back to reference 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 186:195–202PubMedCrossRef 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 186:195–202PubMedCrossRef
Metadata
Title
Myeloid-derived suppressor cells control microbial sepsis
Authors
Marc Derive
Youcef Bouazza
Corentine Alauzet
Sébastien Gibot
Publication date
01-06-2012
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 6/2012
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-012-2574-4

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