Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation

Abstract

Defining critical points of modulation across heterogeneous clinical syndromes may provide insight into new therapeutic approaches. Coagulation initiated by the cytokine-receptor family member known as tissue factor is a hallmark of systemic inflammatory response syndromes in bacterial sepsis and viral haemorrhagic fevers1,2, and anticoagulants can be effective in severe sepsis with disseminated intravascular coagulation3. The precise mechanism coupling coagulation and inflammation remains unresolved4,5,6,7. Here we show that protease-activated receptor 1 (PAR1) signalling sustains a lethal inflammatory response that can be interrupted by inhibition of either thrombin or PAR1 signalling. The sphingosine 1-phosphate (S1P) axis is a downstream component of PAR1 signalling, and by combining chemical and genetic probes for S1P receptor 3 (S1P3) we show a critical role for dendritic cell PAR1–S1P3 cross-talk in regulating amplification of inflammation in sepsis syndrome. Conversely, dendritic cells sustain escalated systemic coagulation and are the primary hub at which coagulation and inflammation intersect within the lymphatic compartment. Loss of dendritic cell PAR1–S1P3 signalling sequesters dendritic cells and inflammation into draining lymph nodes, and attenuates dissemination of interleukin-1β to the lungs. Thus, activation of dendritic cells by coagulation in the lymphatics emerges as a previously unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Coagulation amplifies inflammation and lethality through PAR1 signalling.
Figure 2: PAR1 amplifies inflammation through SphK1–S1P3 signalling crosstalk.
Figure 3: Dendritic cell PAR1–SphK1–S1P3 signalling controls dissemination of inflammation from the lymphatics.
Figure 4: Dendritic cell PAR1–S1P3 signalling promotes disseminated intravascular coagulation and lethality.

Similar content being viewed by others

References

  1. Esmon, C. T. Interactions between the innate immune and blood coagulation systems. Trends Immunol. 25, 536–542 (2004)

    Article  CAS  Google Scholar 

  2. Ruf, W. Emerging roles of tissue factor in viral hemorrhagic fever. Trends Immunol. 25, 461–464 (2004)

    Article  CAS  Google Scholar 

  3. Opal, S. M. The nexus between systemic inflammation and disordered coagulation in sepsis. J. Endotoxin Res. 10, 125–129 (2004)

    Article  CAS  Google Scholar 

  4. Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101, 3765–3777 (2003)

    Article  CAS  Google Scholar 

  5. Taylor, F. B. Staging of the pathophysiologic responses of the primate microvasculature to Escherichia coli and endotoxin: examination of the elements of the compensated response and their links to the corresponding uncompensated lethal variants. Crit. Care Med. 29, S78–S89 (2001)

    Article  Google Scholar 

  6. Pawlinski, R. et al. Role of tissue factor and protease activated receptors in a mouse model of endotoxemia. Blood 103, 1342–1347 (2003)

    Article  Google Scholar 

  7. Camerer, E. et al. Roles of protease-activated receptors in a mouse model of endotoxemia. Blood 107, 3912–3921 (2006)

    Article  CAS  Google Scholar 

  8. Xu, H., Ploplis, V. A. & Castellino, F. J. A coagulation factor VII deficiency protects against acute inflammatory responses in mice. J. Pathol. 210, 488–496 (2006)

    Article  CAS  Google Scholar 

  9. Ahamed, J. et al. Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia. Blood 109, 5251–5259 (2007)

    Article  CAS  Google Scholar 

  10. Rosen, H. & Goetzl, E. J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nature Rev. Immunol. 5, 560–570 (2005)

    Article  CAS  Google Scholar 

  11. Feistritzer, C. & Riewald, M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105, 3178–3184 (2005)

    Article  CAS  Google Scholar 

  12. Singleton, P. A. et al. Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am. J. Respir. Cell Mol. Biol. 37, 222–231 (2007)

    Article  CAS  Google Scholar 

  13. Shortman, K. & Naik, S. H. Steady-state and inflammatory dendritic-cell development. Nature Rev. Immunol. 7, 19–30 (2007)

    Article  CAS  Google Scholar 

  14. Steinman, R. M. & Banchereau, J. Taking dendritic cells into medicine. Nature 449, 419–426 (2007)

    Article  ADS  CAS  Google Scholar 

  15. Randolph, G. J., Angeli, V. & Swartz, M. A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nature Rev. Immunol. 5, 617–628 (2005)

    Article  CAS  Google Scholar 

  16. Czeloth, N. et al. Sphingosine-1-phosphate mediates migration of mature dendritic cells. J. Immunol. 175, 2960–2967 (2005)

    Article  CAS  Google Scholar 

  17. Maeda, Y. et al. Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J. Immunol. 178, 3437–3446 (2007)

    Article  CAS  Google Scholar 

  18. Ferrari, D. et al. The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol. 176, 3877–3883 (2006)

    Article  CAS  Google Scholar 

  19. Baroni, M. et al. Stimulation of P2 (P2X7) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles. FASEB J. 21, 1926–1933 (2007)

    Article  CAS  Google Scholar 

  20. Efron, P. A. et al. Characterization of the systemic loss of dendritic cells in murine lymph nodes during polymicrobial sepsis. J. Immunol. 173, 3035–3043 (2004)

    Article  CAS  Google Scholar 

  21. Scumpia, P. O. et al. CD11c+ dendritic cells are required for survival in murine polymicrobial sepsis. J. Immunol. 175, 3282–3286 (2005)

    Article  CAS  Google Scholar 

  22. Fujita, S. et al. Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response. Blood 107, 3656–3664 (2006)

    Article  CAS  Google Scholar 

  23. Ohteki, T. et al. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo . J. Exp. Med. 203, 2329–2338 (2006)

    Article  CAS  Google Scholar 

  24. Damiano, B. P. et al. Cardiovascular responses mediated by protease-activated receptor- 2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1. J. Pharmacol. Exp. Ther. 288, 671–678 (1999)

    CAS  PubMed  Google Scholar 

  25. Ishii, I. et al. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3. J. Biol. Chem. 276, 33697–33704 (2001)

    Article  CAS  Google Scholar 

  26. Allende, M. L. et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J. Biol. Chem. 279, 52487–52492 (2004)

    Article  CAS  Google Scholar 

  27. Labasi, J. M. et al. Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J. Immunol. 168, 6436–6445 (2002)

    Article  CAS  Google Scholar 

  28. Don, A. S. et al. Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues. J. Biol. Chem. 282, 15833–15842 (2007)

    Article  CAS  Google Scholar 

  29. Pan, S. et al. A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem. Biol. 13, 1227–1234 (2006)

    Article  CAS  Google Scholar 

  30. Lutz, M. B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by NIH grants to W.R. and H.R. and a stipend to F.N. from the Deutsche Forschungsgemeinschaft. The SphK1-/- strain was kindly provided to H.R. by R. Prioa. We thank C. Biazak, J. Royce, P. Tejada and N. Pham-Mitchell for expert technical assistance, and C. Johnson for illustrations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wolfram Ruf.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-6 with Legends and additional references. (PDF 794 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niessen, F., Schaffner, F., Furlan-Freguia, C. et al. Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation. Nature 452, 654–658 (2008). https://doi.org/10.1038/nature06663

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nature06663

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing