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DOI: 10.1160/TH12-11-0859
The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis
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).
Publication History
Received:
23 November 2012
Accepted after minor revision:
25 January 2012
Publication Date:
22 November 2017 (online)
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.
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