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Thromb Haemost 2013; 109(04): 726-737
DOI: 10.1160/TH12-11-0859
Animal Models
Schattauer GmbH

The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis

Liesbeth M. Kager
1   Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
,
Joris J. T. H. Roelofs
4   Department of Pathology, University of Amsterdam, Amsterdam, The Netherlands
,
Alex F. de Vos
1   Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
,
Catharina W. Wieland
1   Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
,
Marcel Schouten
1   Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
,
Joost C. M. Meijers
5   Department of Experimental Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
6   Department of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands
,
Berend Isermann
7   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Germany
,
Cornelis van’t Veer
1   Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
,
Charles T. Esmon
8   Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City, Oklahoma, USA
,
Tom van der Poll
1   Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
3   Center of Experimental and Molecular Medicine (CEMM), 3Department of Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations Financial support: This work was sponsored by research grants of ZonMW (to L. M. K., grant number 92003504), the Stichting BeGeTu (to L. M. K.), the Mr. Willem Bakhuys Roozeboom Stichting (to L. M. K.), the Dutch Kidney Foundation (to J. J. T. H. R., grant number C09.2287) and the Dutch Thrombosis Foundation (to M. S., grant number TSN 2005–1).
Further Information

Publication History

Received: 23 November 2012

Accepted after minor revision: 25 January 2012

Publication Date:
22 November 2017 (online)

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Summary

The protein C (PC) system is an important regulator of both coagulation and inflammation. Activated PC (APC), together with its receptor the endothelial protein C receptor (EPCR), has anticoagulant and anti-inflammatory properties. During tuberculosis (TB), a devastating chronic pulmonary disease caused by Mycobacterium (M.) tuberculosis, both a local inflammatory reaction characterised by the recruitment of mainly mononuclear cells and the formation of pulmonary granulomas as well as activation of coagulation occurs as part of the host immune response. We investigated the role of EPCR and APC in a mouse model of TB using mice overexpressing EPCR (Tie2-EPCR), mice deficient for EPCR (EPCR−/−), mice treated with APC-inhibiting antibodies and mice overexpressing APC (APChigh) and compared them with wild-type (WT) mice. Blood and organs were harvested to quantify bacterial loads, cellular influxes, cytokines, histopathology and coagulation parameters. Additionally observation studies were performed. Lung EPCR expression was upregulated during experimental TB. No significant differences in bacterial growth were seen between WT and Tie2-EPCR mice. However, Tie2-EPCR mice had decreased pulmonary coagulation activation, displayed an increased influx of macro-phages 2 and 6 weeks after infection, but no increase in other proin-flammatory markers. On the other hand, in EPCR−/−-mice coagulation activation was decreased 6 weeks post-infection, with little impact on other inflammation markers. APC-overexpression or treatment with anti-(A)PC antibodies displayed minimal effects during experimental TB. In conclusion, EPCR and APC play a limited role in the host response during experimental pulmonary TB.

Keywords

Tuberculosis - inflammation - activated protein C - endothelial protein C receptor - lung - mice - infection

 

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