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DOI: 10.1160/TH13-10-0859
The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis
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.
Publication History
Received:
19 October 2013
Accepted after minor revision:
10 January 2013
Publication Date:
01 December 2017 (online)
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.
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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.
- 2 File Jr. TM, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgrad Med 2010; 122: 130-141.
- 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.
- 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.
- 5 Schouten M, Wiersinga WJ, Levi M. et al. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83: 536-545.
- 6 Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood 2007; 109: 3161-3172.
- 7 Esmon CT. The endothelial protein C receptor. Curr Opin Hematol 2006; 13: 382-385.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 20 Li W, Zheng X, Gu JM. et al. Extraembryonic Expression of EPCR Is Essential for Embryonic Viability. Blood 2005; 106: 2716-2722.
- 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.
- 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.
- 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.
- 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.
- 25 Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159-175.
- 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.
- 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.
- 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.
- 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.
- 30 Elphick GF, Sarangi PP, Hyun YM. et al. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood 2009; 113: 4078-4085.
- 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.
- 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.