Skip to main content
SpringerLink
Log in

Lipopeptides rather than lipopolysaccharide favor the development of dendritic cell dysfunction similar to polymicrobial sepsis in mice

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

We investigated whether the dysfunction of dendritic cells (DC) that develops during polymicrobial sepsis is mimicked by systemic administration of the Toll-like receptor (TLR) 4 agonist lipopolysaccharide (LPS) or of the TLR2 agonist Pam3-Cys-Ser-Lys4 (P3CSK4).

Materials and methods

BALB/c mice underwent cecal ligation and puncture (CLP) or sham operation or received a single i.p. injection of LPS (30 mg/kg body weight), P3CSK4 (10 mg/kg body weight), or saline as control. Purified splenic DC and in-vitro-generated DC from bone marrow were analyzed in terms of surface marker expression, cytokine secretion, and antigen-specific T-cell activation in vivo.

Results

Splenic DC were suppressed in IL-12 secretion 12 h after LPS and P3CSK4 administration but released increased levels of IL-12 4 days after TLR agonist application, unlike DC from CLP mice. Polymicrobial sepsis and TLR agonists caused a loss of DC in the spleen but led to the expansion of diverse DC subsets. DC that differentiated from bone marrow after P3CSK4 but not after LPS application resembled DC from CLP mice regarding cytokine secretion and impaired Th1-cell polarization.

Conclusions

The development of DC dysfunction during sepsis is at least partly mimicked by TLR2 agonists rather than TLR4 agonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.

    Article  PubMed  CAS  Google Scholar 

  2. Benjamim CF, Hogaboam CM, Kunkel SL. The chronic consequences of severe sepsis. J Leukoc Biol. 2004;75:408–12.

    Article  PubMed  CAS  Google Scholar 

  3. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.

    Article  PubMed  CAS  Google Scholar 

  4. Chen M, Huang L, Shabier Z, Wang J. Regulation of the lifespan in dendritic cell subsets. Mol Immunol. 2007;44:2558–65.

    Article  PubMed  CAS  Google Scholar 

  5. Kamath AT, Pooley J, O’Keeffe MA, Vremec D, Zhan Y, Lew AM, et al. The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J Immunol. 2000;165:6762–70.

    PubMed  CAS  Google Scholar 

  6. Edwards AD, Manickasingham SP, Sporri R, Diebold SS, Schulz O, Sher A, et al. Microbial recognition via Toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering. J Immunol. 2002;169:3652–60.

    PubMed  CAS  Google Scholar 

  7. Moser M, Murphy KM. Dendritic cell regulation of TH1-TH2 development. Nat Immunol. 2000;1:199–205.

    Article  PubMed  CAS  Google Scholar 

  8. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180:5771–7.

    PubMed  CAS  Google Scholar 

  9. Flohé SB, Agrawal H, Schmitz D, Gertz M, Flohé S, Schade FU. Dendritic cells during polymicrobial sepsis rapidly mature but fail to initiate a protective Th1-type immune response. J Leukoc Biol. 2006;79:473–81.

    Article  PubMed  Google Scholar 

  10. Efron PA, Martins A, Minnich D, Tinsley K, Ungaro R, Bahjat FR, et al. Characterization of the systemic loss of dendritic cells in murine lymph nodes during polymicrobial sepsis. J Immunol. 2004;173:3035–43.

    PubMed  CAS  Google Scholar 

  11. Flohé SB, Agrawal H, Flohé S, Rani M, Bangen JM, Schade FU. Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med. 2008;14:247–56.

    Article  PubMed  Google Scholar 

  12. Pastille E, Didovic S, Brauckmann D, Rani M, Agrawal H, Schade FU, et al. Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after polymicrobial sepsis. J Immunol. 2011;186:977–86.

    Article  PubMed  CAS  Google Scholar 

  13. Reis e Sousa C. Toll-like receptors and dendritic cells: for whom the bug tolls. Semin Immunol. 2004;16:27–34.

    Article  PubMed  CAS  Google Scholar 

  14. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–87.

    Article  PubMed  CAS  Google Scholar 

  15. Yanagawa Y, Onoe K. Enhanced IL-10 production by TLR4- and TLR2-primed dendritic cells upon TLR restimulation. J Immunol. 2007;178:6173–80.

    PubMed  CAS  Google Scholar 

  16. Bagchi A, Herrup EA, Warren HS, Trigilio J, Shin HS, Valentine C, et al. MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J Immunol. 2007;178:1164–71.

    PubMed  CAS  Google Scholar 

  17. Sparwasser T, Miethke T, Lipford G, Borschert K, Hacker H, Heeg K, et al. Bacterial DNA causes septic shock. Nature. 1997;386:336–7.

    Article  PubMed  CAS  Google Scholar 

  18. Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223:77–92.

    Article  PubMed  CAS  Google Scholar 

  19. Penè F, Zuber B, Courtine E, Rousseau C, Ouaaz F, Toubiana J, et al. Dendritic cells modulate lung response to Pseudomonas aeruginosa in a murine model of sepsis-induced immune dysfunction. J Immunol. 2008;181:8513–20.

    PubMed  Google Scholar 

  20. Tinsley KW, Grayson MH, Swanson PE, Drewry AM, Chang KC, Karl IE, et al. Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. J Immunol. 2003;171:909–14.

    PubMed  CAS  Google Scholar 

  21. De Trez C, Pajak B, Brait M, Glaichenhaus N, Urbain J, Moser M, et al. TLR4 and Toll-IL-1 receptor domain-containing adapter-inducing IFN-beta, but not MyD88, regulate Escherichia coli-induced dendritic cell maturation and apoptosis in vivo. J Immunol. 2005;175:839–46.

    PubMed  Google Scholar 

  22. Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, et al. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science. 1999;285:736–9.

    Article  PubMed  CAS  Google Scholar 

  23. Penè F, Courtine E, Ouaaz F, Zuber B, Sauneuf B, Sirgo G, et al. Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells. Infect Immun. 2009;77:5651–8.

    Article  PubMed  Google Scholar 

  24. Muenzer JT, Davis CG, Dunne BS, Unsinger J, Dunne WM, Hotchkiss RS. Pneumonia after cecal ligation and puncture: a clinically relevant “two-hit” model of sepsis. Shock. 2006;26:565–70.

    Article  PubMed  Google Scholar 

  25. Murphey ED, Lin CY, McGuire RW, Toliver-Kinsky T, Herndon DN, Sherwood ER. Diminished bacterial clearance is associated with decreased IL-12 and interferon-gamma production but a sustained proinflammatory response in a murine model of postseptic immunosuppression. Shock. 2004;21:415–25.

    Article  PubMed  CAS  Google Scholar 

  26. Dillon S, Agrawal A, Van Dyke T, Landreth G, McCauley L, Koh A, et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol. 2004;172:4733–43.

    PubMed  CAS  Google Scholar 

  27. De Smedt T, Pajak B, Muraille E, Lespagnard L, Heinen E, De Baetselier P, et al. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med. 1996;184:1413–24.

    Article  PubMed  Google Scholar 

  28. Kaisho T, Takeuchi O, Kawai T, Hoshino K, Akira S. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J Immunol. 2001;166:5688–94.

    PubMed  CAS  Google Scholar 

  29. Wysocka M, Robertson S, Riemann H, Caamano J, Hunter C, Mackiewicz A, et al. IL-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness. J Immunol. 2001;166:7504–13.

    PubMed  CAS  Google Scholar 

  30. Wen H, Dou Y, Hogaboam CM, Kunkel SL. Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood. 2008;111:1797–804.

    Article  PubMed  CAS  Google Scholar 

  31. Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity. 2006;24:801–12.

    Article  PubMed  CAS  Google Scholar 

  32. Fujita S, Seino K, Sato K, Sato Y, Eizumi K, Yamashita N, et al. Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response. Blood. 2006;107:3656–64.

    Article  PubMed  CAS  Google Scholar 

  33. Stoll S, Jonuleit H, Schmitt E, Muller G, Yamauchi H, Kurimoto M, et al. Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development. Eur J Immunol. 1998;28:3231–9.

    Article  PubMed  CAS  Google Scholar 

  34. Penè F, Grimaldi D, Zuber B, Sauneuf B, Rousseau C, El Hachem C, et al. Toll-like receptor 2 deficiency increases resistance to Pseudomonas aeruginosa pneumonia in the setting of sepsis-induced immune dysfunction. J Infect Dis. 2012;206:932–42.

    Article  PubMed  Google Scholar 

  35. Bessler WG, Mittenbuhler K, Esche U, Huber M. Lipopeptide adjuvants in combination treatment. Int Immunopharmacol. 2003;3:1217–24.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Michaela Bak for excellent technical assistance. This work was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG, GK1045) to S. B. Flohé.

Author information

Authors and Affiliations

  1. Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Virchowstr. 171, 45147, Essen, Germany

    Stephanie Bruns, Eva Pastille, Florian Wirsdörfer, Marion Frisch & Stefanie B. Flohé

Authors
  1. Stephanie Bruns
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva Pastille
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florian Wirsdörfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marion Frisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefanie B. Flohé
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefanie B. Flohé.

Additional information

Responsible Editor: Artur Bauhofer.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 33 kb)

Supplementary material 2 (PDF 15 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bruns, S., Pastille, E., Wirsdörfer, F. et al. Lipopeptides rather than lipopolysaccharide favor the development of dendritic cell dysfunction similar to polymicrobial sepsis in mice. Inflamm. Res. 62, 627–636 (2013). https://doi.org/10.1007/s00011-013-0616-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-013-0616-1

Keywords

Search

Navigation