Thromb Haemost 2019; 119(06): 930-940
DOI: 10.1055/s-0039-1681046
Blood Cells, Inflammation and Infection
Georg Thieme Verlag KG Stuttgart · New York

Platelet Btk is Required for Maintaining Lung Vascular Integrity during Murine Pneumococcal Pneumosepsis

Alexander P. N. A. de Porto*
1  Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2  Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Amsterdam, The Netherlands
,
Theodora A. M. Claushuis*
1  Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2  Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Amsterdam, The Netherlands
,
Lieve E. H. van der Donk
1  Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2  Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Amsterdam, The Netherlands
,
Regina de Beer
1  Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2  Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Amsterdam, The Netherlands
,
Onno J. de Boer
3  Department of Pathology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Sandrine Florquin
3  Department of Pathology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Joris J. T. H. Roelofs
3  Department of Pathology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Rudi W. Hendriks
4  Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands
,
Tom van der Poll
1  Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2  Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Amsterdam, The Netherlands
5  Division of Infectious Diseases, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Cornelis van't Veer
1  Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2  Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Amsterdam, The Netherlands
,
Alex F. de Vos
1  Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2  Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Amsterdam, The Netherlands
› Author Affiliations
Funding A.P.N.A. de Porto was funded by a PhD scholarship from the Academic Medical Center, Amsterdam, the Netherlands. T.A.M.C. was funded by a grant from the Landsteiner Foundation for Blood Transfusion research (LSBR grand 1351).
Further Information

Publication History

12 July 2018

20 January 2019

Publication Date:
14 March 2019 (online)

Abstract

Platelet Bruton's tyrosine kinase (Btk) is an essential signalling protein for the collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type-lectin-like receptor-2, which are platelet receptors implicated in the maintenance of vascular integrity during inflammation. Moreover, platelets, platelet GPVI and Btk are important for host defence during murine bacterial pneumosepsis. The aim of this study was to determine the role of platelet Btk in vascular integrity and host defence during murine pneumosepsis caused by the common human pathogens Streptococcus pneumoniae and Klebsiella pneumoniae. Using the Cre-loxP system, male platelet-specific Btk-deficient mice (PF4creBtkfl/Y) were created. Similar to platelets from total Btk-deficient mice, platelets from PF4creBtkfl/Y mice showed abrogated aggregation and P-selectin expression when stimulated with the GPVI ligand cross-linked collagen-related peptide. Upon infection with S. pneumoniae, PF4creBtkfl/Y mice showed increased lung bleeding, but unimpaired anti-bacterial defence. During pneumosepsis evoked by K. pneumoniae, platelet Btk deficiency was not associated with lung bleeding and did not impact on host defence, even when platelet function was further compromised by blocking secondary platelet activation by the P2Y12 receptor antagonist clopidogrel. Together, these data indicate that, while platelet Btk is not important for anti-bacterial defence in pneumosepsis, its role in maintaining vascular integrity in the lung depends on the causative pathogen.

* A.P.N.A. de Porto and T.A.M.C. contributed equally to this work.


Supplementary Material