Protease activated receptor 4 limits bacterial growth and lung pathology during late stage Streptococcus pneumoniae induced pneumonia in mice

Sacha F. de Stoppelaar; Cornelis van ’t Veer; Florry E. van den Boogaard; Rienk Nieuwland; Arie J. Hoogendijk; Onno J. de Boer; Joris J. T. H. Roelofs; Tom van der Poll

doi:10.1160/TH13-01-0052

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(03): 582-592
DOI: 10.1160/TH13-01-0052

Wound Healing and Inflammation/Infection

Schattauer GmbH

Protease activated receptor 4 limits bacterial growth and lung pathology during late stage Streptococcus pneumoniae induced pneumonia in mice

Sacha F. de Stoppelaar

¹Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

²Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

,

Cornelis van ’t Veer

¹Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

²Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

,

Florry E. van den Boogaard

¹Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

²Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

,

Rienk Nieuwland

⁴Laboratory for Experimental Clinical Chemistry (LEKC), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

,

Arie J. Hoogendijk

¹Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

²Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

,

Onno J. de Boer

³Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

,

Joris J. T. H. Roelofs

³Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

,

Tom van der Poll

¹Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

²Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

⁵Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

› Author Affiliations

Abstract

Summary

Streptococcus pneumoniae is a common causative pathogen of pneumonia and sepsis. Pneumonia and sepsis are associated with enhanced activation of coagulation, resulting in the production of several host-derived proteases at the primary site of infection and in the circulation. Serine proteases cleave protease activated receptors (PARs), which form a molecular link between coagulation and inflammation. PAR4 is one of four subtypes of PARs and is widely expressed by multiple cell types in the respiratory tract implicated in pulmonary inflammation, by immune cells and by platelets. In mice, mouse (m)PAR4 is the only thrombin receptor expressed by platelets. We here sought to determine the contribution of mPAR4 to the host response during pneumococcal pneumonia. Pneumonia was induced by intranasal inoculation with S. pneumoniae in mPAR4-deficient (par4^-/- ) and wild-type mice. Mice were sacrificed after 6, 24 or 48 hours (h). Blood, lungs, liver and spleen were collected for analyses. Ex vivo stimulation assays were performed with S. pneumoniae and mPAR4 activating peptides. At 48 h after infection, higher bacterial loads were found in the lungs and blood of par4^-/- mice (p < 0.05), accompanied by higher histopathology scores and increased cytokine levels (p < 0.05) in the lungs. Ex vivo, co-stimulation with mPAR4 activating peptide enhanced the whole blood cytokine response to S. pneumoniae. Thrombin inhibition resulted in decreased cytokine release after S. pneumoniae stimulation in human whole blood. Our findings suggest that mPAR4 contributes to antibacterial defence during murine pneumococcal pneumonia.

Keywords

Protease activated receptors - Streptococcus pneumoniae - thrombin - platelet immunology - infectious diseases

Full Text

References

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