Inflammation Research

, Volume 60, Issue 3, pp 271–279 | Cite as

Stimulation of TLR7 prior to polymicrobial sepsis improves the immune control of the inflammatory response in adult mice

  • P. KoernerEmail author
  • T. Traeger
  • H. Mehmcke
  • K. Cziupka
  • W. Kessler
  • A. Busemann
  • S. Diedrich
  • G. Hartmann
  • C.-D. Heidecke
  • S. Maier
Original Research Paper



The role of Toll-like receptor 7 (TLR7), so far regarded as a receptor for viral RNA, was evaluated in a murine sepsis model.


We used the colon ascendens stent peritonitis model (CASP) in female C57B/6 mice. R-848 (1.5 μg/g body weight) was injected intravenously prior to sepsis induction.


We determined levels of cytokines by CBA detection kit. Different cell populations were isolated from the spleen by magnetic cell separation and the expression of TLR7 was visualized by immunofluorescence staining. Bacterial load of organs was quantified by incubating suspensions on agar in colony forming units.


R-848 application per se led to elevated cytokine levels in serum, spleen and peritoneal cavity. Expression of TLR7 on splenocytes was upregulated following CASP. Bacterial clearance in polymicrobial sepsis was significantly increased in spleen and peritoneum of mice pre-treated with the TLR7-agonist. Cytokine release was regulated in the peritoneum and spleen. Furthermore, apoptosis in thymus and spleen during polymicrobial sepsis was significantly decreased following TLR7 agonist application.


TLR7 seems to be essential for pathogen defence not only in viral but also in bacterial infections. Pharmacological stimulation of this receptor prior to induction of sepsis improves the host’s capacity to cope with pathogens.


CASP Toll like receptor R-848 Resiquimod Sepsis 



We thank Kathrin Mülling and Antje Janetzko for excellent technical assistance and Robert Jack for critical reading of the manuscript. Hendrik Mehmcke was supported in the graduate school GRK 840 (Host-pathogen interactions) by a predoctoral fellowship from Deutsche Forschungsgemeinschaft (DFG).

Conflict of interest

No conflicts of interest exist.


  1. 1.
    Warren HS. Toll-like receptors. Crit Care Med. 2005;33(12 Suppl):457–9.CrossRefGoogle Scholar
  2. 2.
    Sioud M. Innate sensing of self and non-self RNAs by Toll-like receptors. Trends Mol Med. 2006;12(4):167–76.CrossRefPubMedGoogle Scholar
  3. 3.
    Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–80.CrossRefPubMedGoogle Scholar
  4. 4.
    Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell. 1998;2(2):253–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Feterowski C, Novotny A, Kaiser-Moore S, Muhlradt PF, Rossmann-Bloeck T, Rump M, et al. Attenuated pathogenesis of polymicrobial peritonitis in mice after TLR2 agonist pre-treatment involves ST2 up-regulation. Int Immunol. 2005;17(8):1035–46.CrossRefPubMedGoogle Scholar
  6. 6.
    Salomao R, Martins PS, Brunialti MK, Fernandes ML, Martos LS, Mendes ME, et al. TLR signaling pathway in patients with sepsis. Shock. 2008;30:73–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303(5663):1526–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Hornung V, Barchet W, Schlee M, Hartmann G. RNA recognition via TLR7 and TLR8. Handb Exp Pharmacol. 2008;183:71–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3(2):196–200.CrossRefPubMedGoogle Scholar
  10. 10.
    Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol. 2002;3(6):499.CrossRefPubMedGoogle Scholar
  11. 11.
    Testerman TL, Gerster JF, Imbertson LM, Reiter MJ, Miller RL, Gibson SJ, et al. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol. 1995;58(3):365–72.PubMedGoogle Scholar
  12. 12.
    Sato S, Takeuchi O, Fujita T, Tomizawa H, Takeda K, Akira S. A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways. Int Immunol. 2002;14(7):783–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Feterowski C, Weighardt H, Emmanuilidis K, Hartung T, Holzmann B. Immune protection against septic peritonitis in endotoxin-primed mice is related to reduced neutrophil apoptosis. Eur J Immunol. 2001;31(4):1268–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Maier S, Traeger T, Entleutner M, Westerholt A, Kleist B, Huser N, et al. Cecal ligation and puncture versus colon ascendens stent peritonitis: two distinct animal models for polymicrobial sepsis. Shock. 2004;21(6):505–11.CrossRefPubMedGoogle Scholar
  15. 15.
    Zantl N, Uebe A, Neumann B, Wagner H, Siewert JR, Holzmann B, et al. Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis. Infect Immun. 1998;66(5):2300–9.PubMedGoogle Scholar
  16. 16.
    Hensler T, Heidecke CD, Hecker H, Heeg K, Bartels H, Zantl N, et al. Increased susceptibility to postoperative sepsis in patients with impaired monocyte IL-12 production. J Immunol. 1998;161(5):2655–9.PubMedGoogle Scholar
  17. 17.
    Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7(2):131–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Delgado MA, Elmaoued RA, Davis AS, Kyei G, Deretic V. Toll-like receptors control autophagy. EMBO J. 2008;27(7):1110–21.CrossRefPubMedGoogle Scholar
  19. 19.
    Weighardt H, Feterowski C, Veit M, Rump M, Wagner H, Holzmann B. Increased resistance against acute polymicrobial sepsis in mice challenged with immunostimulatory CpG oligodeoxynucleotides is related to an enhanced innate effector cell response. J Immunol. 2000;165(8):4537–43.PubMedGoogle Scholar
  20. 20.
    Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009;157(7):1250–62.CrossRefPubMedGoogle Scholar
  21. 21.
    Buttenschoen K, Schneider ME, Utz K, Kornmann M, Beger HG, Carli BD. Effect of major abdominal surgery on endotoxin release and expression of Toll-like receptors 2/4. Langenbecks Arch Surg. 2009;394(2):293–302.CrossRefPubMedGoogle Scholar
  22. 22.
    Palazzo M, Gariboldi S, Zanobbio L, Dusio GF, Selleri S, Bedoni M, et al. Cross-talk among Toll-like receptors and their ligands. Int Immunol. 2008;20(5):709–18.CrossRefPubMedGoogle Scholar
  23. 23.
    Wynn JL, Scumpia PO, Winfield RD, Delano MJ, Kelly-Scumpia K, Barker T, et al. Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood. 2008;112(5):1750–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Busse M, Traeger T, Potschke C, Billing A, Dummer A, Friebe E, et al. Detrimental role for CD4+ T lymphocytes in murine diffuse peritonitis due to inhibition of local bacterial elimination. Gut. 2008;57(2):188–95.CrossRefPubMedGoogle Scholar
  25. 25.
    Traeger T, Kessler W, Assfalg V, Cziupka K, Koerner P, Dassow C, et al. Detrimental role of CC chemokine receptor 4 in murine polymicrobial sepsis. Infect Immun. 2008;76(11):5285–93.CrossRefPubMedGoogle Scholar
  26. 26.
    Cavaillon JM, Annane D. Compartmentalization of the inflammatory response in sepsis and SIRS. J Endotoxin Res. 2006;12(3):151–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Paul-Clark MJ, McMaster SK, Belcher E, Sorrentino R, Anandarajah J, Fleet M, et al. Differential effects of Gram-positive versus Gram-negative bacteria on NOSII and TNFalpha in macrophages: role of TLRs in synergy between the two. Br J Pharmacol. 2006;148(8):1067–75.CrossRefPubMedGoogle Scholar
  28. 28.
    Ulloa L, Tracey KJ. The “cytokine profile”: a code for sepsis. Trends Mol Med. 2005;11(2):56–63.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • P. Koerner
    • 1
    Email author
  • T. Traeger
    • 1
  • H. Mehmcke
    • 1
  • K. Cziupka
    • 1
  • W. Kessler
    • 1
  • A. Busemann
    • 1
  • S. Diedrich
    • 1
  • G. Hartmann
    • 2
  • C.-D. Heidecke
    • 1
  • S. Maier
    • 1
  1. 1.Department of Surgery, General Surgery, Visceral, Thoracical and Vascular SurgeryErnst Moritz Arndt UniversitätGreifswaldGermany
  2. 2.Institute of Clinical PharmacologyRheinische Friedrich-Wilhelms-UniversitätBonnGermany

Personalised recommendations