Download PDF
Thromb Haemost 2014; 111(05): 970-980
DOI: 10.1160/TH13-10-0859
Animal Models
Schattauer GmbH

The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis

Marcel Schouten
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
J. Daan de Boer
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Liesbeth M. Kager
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3   Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Joris J. T. H. Roelofs
4   Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Joost C. M. Meijers
5   Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Charles T. Esmon
6   Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
,
Marcel Levi
3   Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Cornelis van ’t Veer
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Tom van der Poll
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3   Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations Financial support: Marcel Schouten is supported by a research grant of the Dutch Thrombosis Foundation [grant number TSN 2005–1]. J. Daan de Boer is supported by a research grant of the Netherlands Asthma Foundation (project 3.2.08.009). L.M. Kager is supported by research grants of ZonMW (grant number 92003504), the Stichting BeGeTu and the Mr. Willem Bakhuys Roozeboom Stichting.
Further Information

Publication History

Received: 19 October 2013

Accepted after minor revision: 10 January 2013

Publication Date:
01 December 2017 (online)

    Permissions and Reprints

Summary

Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2-EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR-overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response.

Keywords

Coagulation - endothelial protein C receptor - pneumonia - sepsis - Streptococcus pneumoniae

 

  • References

  • 1 Mandell LA, Wunderink RG, Anzueto A. et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 (Suppl. 02) S27-72.
    CrossrefPubMedGoogle Scholar
  • 2 File Jr. TM, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgrad Med 2010; 122: 130-141.
    CrossrefPubMedGoogle Scholar
  • 3 Laterre PF, Garber G, Levy H. et al. Severe community-acquired pneumonia as a cause of severe sepsis: Data from the PROWESS study. Crit Care Med 2005; 33: 952-961.
    CrossrefPubMedGoogle Scholar
  • 4 Bartlett JG, Dowell SF, Mandell LA. et al. Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 2000; 31: 347-382.
    CrossrefPubMedGoogle Scholar
  • 5 Schouten M, Wiersinga WJ, Levi M. et al. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83: 536-545.
    CrossrefPubMedGoogle Scholar
  • 6 Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood 2007; 109: 3161-3172.
    CrossrefPubMedGoogle Scholar
  • 7 Esmon CT. The endothelial protein C receptor. Curr Opin Hematol 2006; 13: 382-385.
    CrossrefPubMedGoogle Scholar
  • 8 Taylor Jr. FB, Peer GT, Lockhart MS. et al. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 2001; 97: 1685-1688.
    CrossrefPubMedGoogle Scholar
  • 9 Burnier L, Mosnier LO. Novel mechanisms for activated protein C cytoprotective activities involving non-canonical activation of protease-activated receptor 3. Blood. 2013 Epub ahead of print.
    PubMedGoogle Scholar
  • 10 Schouten M, van ’t Veer C, van den Boogaard FE. et al. Therapeutic recombinant murine activated protein C attenuatues pulmonary coagulopathy and improves survival in murine pneumococcal pneumonia. J Infect Dis 2010; 202: 1600-1607.
    CrossrefPubMedGoogle Scholar
  • 11 Schouten M, van ’t Veer C, Roelofs JJ. et al. Recombinant human activated protein C attenuates coagulopathy and inflammation when administered early in murine pneumococcal pneumonia. Thromb Haemost 2011; 106: 1189-1196.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Laszik Z, Mitro A, Taylor Jr. FB. et al. Human Protein C Receptor Is Present Primarily on Endothelium of Large Blood Vessels: Implications for the Control of the Protein C Pathway. Circulation 1997; 96: 3633-3640.
    CrossrefPubMedGoogle Scholar
  • 13 Gleeson EM, O'Donnell JS, Preston RJ. The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signalling. Cell Mol Life Sci 2011; 69: 717-726.
    CrossrefPubMedGoogle Scholar
  • 14 Lattenist L, Kers J, Ten Berge IJ. et al. Renal and urinary levels of EPCR correlate with acute renal allograft rejection. PLoS One 2013; 08: e64994.
    CrossrefPubMedGoogle Scholar
  • 15 Taylor Jr. FB, Stearns-Kurosawa DJ, Kurosawa S. et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95: 1680-1686.
    CrossrefPubMedGoogle Scholar
  • 16 Zheng X, Li W, Song Y. et al. Non-Hematopoietic EPCR Regulates the Coagulation and Inflammatory Responses During Endotoxemia. J Thromb Haemost 2007; 05: 1394-1400.
    CrossrefPubMedGoogle Scholar
  • 17 Li W, Zheng X, Gu J. et al. Overexpressing Endothelial Cell Protein C Receptor Alters the Hemostatic Balance and Protects Mice From Endotoxin. J Thromb Haemost 2005; 03: 1351-1359.
    CrossrefPubMedGoogle Scholar
  • 18 Kager LM, Schouten M, Wiersinga WJ. et al. Overexpression of the Endothelial Protein C Receptor Is Detrimental during Pneumonia-Derived Gram-negative Sepsis (Melioidosis). PLoS Negl Trop Dis 2013; 07: e2306.
    CrossrefPubMedGoogle Scholar
  • 19 Kager LM, Roelofs JJTH, Wieland CW. et al. The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis. Thromb Haemost 2013; 109: 726-737.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Li W, Zheng X, Gu JM. et al. Extraembryonic Expression of EPCR Is Essential for Embryonic Viability. Blood 2005; 106: 2716-2722.
    CrossrefPubMedGoogle Scholar
  • 21 Rijneveld AW, Levi M, Florquin S. et al. Urokinase Receptor Is Necessary for Adequate Host Defense Against Pneumococcal Pneumonia. J Immunol 2002; 168: 3507-3511.
    CrossrefPubMedGoogle Scholar
  • 22 Van der Windt GJ, Hoogendijk AJ, Schouten M. et al. Osteopontin Impairs Host Defense During Pneumococcal Pneumonia. J Infect Dis 2011; 203: 1850-1858.
    CrossrefPubMedGoogle Scholar
  • 23 Knapp S, Wieland CW, Florquin S. et al. Differential Roles of CD14 and Toll-Like Receptors 4 and 2 in Murine Acinetobacter Pneumonia. Am J Respir Crit Care Med 2006; 173: 122-129.
    CrossrefPubMedGoogle Scholar
  • 24 Crawley JT, Gu JM, Ferrell G. et al. Distribution of Endothelial Cell Protein C/Activated Protein C Receptor (EPCR) During Mouse Embryo Development. Thromb Haemost 2002; 88: 259-266.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159-175.
    CrossrefPubMedGoogle Scholar
  • 26 Mollica LR, Crawley JT, Liu K. et al. Role of a 5' -Enhancer in the Transcriptional Regulation of the Human Endothelial Cell Protein C Receptor Gene. Blood 2006; 108: 1251-1259.
    CrossrefPubMedGoogle Scholar
  • 27 Sun H, Wang X, Degen JL. et al. Reduced thrombin generation increases host susceptibility to group A streptococcal infection. Blood 2009; 113: 1358-1364.
    CrossrefPubMedGoogle Scholar
  • 28 Finigan JH, Boueiz A, Wilkinson E. et al. Activated protein C protects against ventilator-induced pulmonary capillary leak. Am J Physiol Lung Cell Mol Physiol 2009; 296: L1002-1011.
    CrossrefPubMedGoogle Scholar
  • 29 Iwaki T, Cruz DT, Martin JA. et al. A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse. Blood 2005; 105: 2364-2371.
    CrossrefPubMedGoogle Scholar
  • 30 Elphick GF, Sarangi PP, Hyun YM. et al. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood 2009; 113: 4078-4085.
    CrossrefPubMedGoogle Scholar
  • 31 Nick JA, Coldren CD, Geraci MW. et al. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 2004; 104: 3878-3885.
    CrossrefPubMedGoogle Scholar
  • 32 Kager LM, de Boer JD, Bresser P. et al. Intrabronchial activated protein C enhances lipopolysaccharide-induced pulmonary responses. Eur Respir J 2013; 42: 188-197.
    CrossrefPubMedGoogle Scholar