RSS-Feed abonnieren
DOI: 10.1055/s-0039-1681046
Platelet Btk is Required for Maintaining Lung Vascular Integrity during Murine Pneumococcal Pneumosepsis
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).Publikationsverlauf
12. Juli 2018
20. Januar 2019
Publikationsdatum:
14. März 2019 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201906/lookinside/thumbnails/10-1055-s-0039-1681046_180490-1.jpg)
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.
-
References
- 1 Ho-Tin-Noé B, Boulaftali Y, Camerer E. Platelets and vascular integrity: how platelets prevent bleeding in inflammation. Blood 2018; 131 (03) 277-288
- 2 de Stoppelaar SF, van 't Veer C, van der Poll T. The role of platelets in sepsis. Thromb Haemost 2014; 112 (04) 666-677
- 3 Yeaman MR. Platelets: at the nexus of antimicrobial defence. Nat Rev Microbiol 2014; 12 (06) 426-437
- 4 Gaertner F, Ahmad Z, Rosenberger G. , et al. Migrating platelets are mechano-scavengers that collect and bundle bacteria. Cell 2017; 171 (06) 1368-1382
- 5 Nieswandt B, Brakebusch C, Bergmeier W. , et al. Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. EMBO J 2001; 20 (09) 2120-2130
- 6 Inoue O, Suzuki-Inoue K, McCarty OJ. , et al. Laminin stimulates spreading of platelets through integrin alpha6beta1-dependent activation of GPVI. Blood 2006; 107 (04) 1405-1412
- 7 Alshehri OM, Hughes CE, Montague S. , et al. Fibrin activates GPVI in human and mouse platelets. Blood 2015; 126 (13) 1601-1608
- 8 Rayes J, Lax S, Wichaiyo S. , et al. The podoplanin-CLEC-2 axis inhibits inflammation in sepsis. Nat Commun 2017; 8 (01) 2239
- 9 D' Atri LP, Schattner M. Platelet Toll-like receptors in thromboinflammation. Front Biosci 2017; 22: 1867-1883
- 10 Hillgruber C, Pöppelmann B, Weishaupt C. , et al. Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia. J Exp Med 2015; 212 (08) 1255-1266
- 11 Boulaftali Y, Hess PR, Getz TM. , et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest 2013; 123 (02) 908-916
- 12 Rayes J, Jadoui S, Lax S. , et al. The contribution of platelet glycoprotein receptors to inflammatory bleeding prevention is stimulus and organ dependent. Haematologica 2018; 103 (06) e256-e258
- 13 van den Boogaard FE, Schouten M, de Stoppelaar SF. , et al. Thrombocytopenia impairs host defense during murine Streptococcus pneumoniae pneumonia. Crit Care Med 2015; 43 (03) e75-e83
- 14 de Stoppelaar SF, van 't Veer C, Claushuis TA, Albersen BJ, Roelofs JJ, van der Poll T. Thrombocytopenia impairs host defense in Gram-negative pneumonia-derived sepsis in mice. Blood 2014; 124 (25) 3781-3790
- 15 Musher DM, Thorner AR. Community-acquired pneumonia. N Engl J Med 2014; 371 (17) 1619-1628
- 16 Paczosa MK, Mecsas J. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev 2016; 80 (03) 629-661
- 17 Bobe R, Wilde JI, Maschberger P. , et al. Phosphatidylinositol 3-kinase-dependent translocation of phospholipase Cgamma2 in mouse megakaryocytes is independent of Bruton tyrosine kinase translocation. Blood 2001; 97 (03) 678-684
- 18 López-Herrera G, Vargas-Hernández A, González-Serrano ME. , et al. Bruton's tyrosine kinase--an integral protein of B cell development that also has an essential role in the innate immune system. J Leukoc Biol 2014; 95 (02) 243-250
- 19 Winkelstein JA, Marino MC, Lederman HM. , et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006; 85 (04) 193-202
- 20 Yother J, Forman C, Gray BM, Briles DE. Protection of mice from infection with Streptococcus pneumoniae by anti-phosphocholine antibody. Infect Immun 1982; 36 (01) 184-188
- 21 Quek LS, Bolen J, Watson SP. A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen. Curr Biol 1998; 8 (20) 1137-1140
- 22 Manne BK, Badolia R, Dangelmaier C. , et al. Distinct pathways regulate Syk protein activation downstream of immune tyrosine activation motif (ITAM) and hemITAM receptors in platelets. J Biol Chem 2015; 290 (18) 11557-11568
- 23 Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. Blood 2006; 108 (08) 2596-2603
- 24 Soriani A, Moran B, de Virgilio M. , et al. A role for PKCtheta in outside-in α(IIb)β3 signaling. J Thromb Haemost 2006; 4 (03) 648-655
- 25 Murthy P, Durco F, Miller-Ocuin JL. , et al. The NLRP3 inflammasome and Bruton's tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation. Biochem Biophys Res Commun 2017; 483 (01) 230-236
- 26 Ito M, Shichita T, Okada M. , et al. Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun 2015; 6: 7360
- 27 Claushuis TAM, de Vos AF, Nieswandt B. , et al. Platelet glycoprotein VI aids in local immunity during gram-negative pneumonia derived sepsis. Blood 2018; 131 (08) 864-876
- 28 Weiser JN, Ferreira DM, Paton JC. Streptococcus pneumoniae: transmission, colonization and invasion. Nat Rev Microbiol 2018; 16 (06) 355-367
- 29 Eddens T, Kolls JK. Host defenses against bacterial lower respiratory tract infection. Curr Opin Immunol 2012; 24 (04) 424-430
- 30 Hendriks RW, de Bruijn MF, Maas A, Dingjan GM, Karis A, Grosveld F. Inactivation of Btk by insertion of lacZ reveals defects in B cell development only past the pre-B cell stage. EMBO J 1996; 15 (18) 4862-4872
- 31 Lammers AJ, de Porto AP, Florquin S. , et al. Enhanced vulnerability for Streptococcus pneumoniae sepsis during asplenia is determined by the bacterial capsule. Immunobiology 2011; 216 (08) 863-870
- 32 Claushuis TA, de Stoppelaar SF, Stroo I. , et al. Thrombin contributes to protective immunity in pneumonia-derived sepsis via fibrin polymerization and platelet-neutrophil interactions. J Thromb Haemost 2017; 15 (04) 744-757
- 33 Claushuis TAM, van der Donk LEH, Luitse AL. , et al. Role of peptidylarginine deiminase 4 in neutrophil extracellular trap formation and host defense during Klebsiella pneumoniae-induced pneumonia-derived sepsis. J Immunol 2018; 201 (04) 1241-1252
- 34 Hoogendijk AJ, Roelofs JJ, Duitman J. , et al. R-roscovitine reduces lung inflammation induced by lipoteichoic acid and Streptococcus pneumoniae. Mol Med 2012; 18: 1086-1095
- 35 Cortjens B, de Boer OJ, de Jong R. , et al. Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease. J Pathol 2016; 238 (03) 401-411
- 36 Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk. Blood 2003; 102 (10) 3592-3599
- 37 Kamel S, Horton L, Ysebaert L. , et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia 2015; 29 (04) 783-787
- 38 Lee RH, Piatt R, Conley PB, Bergmeier W. Effects of ibrutinib treatment on murine platelet function during inflammation and in primary hemostasis. Haematologica 2017; 102 (03) e89-e92
- 39 Savi P, Zachayus JL, Delesque-Touchard N. , et al. The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci U S A 2006; 103 (29) 11069-11074
- 40 Gros A, Syvannarath V, Lamrani L. , et al. Single platelets seal neutrophil-induced vascular breaches via GPVI during immune-complex-mediated inflammation in mice. Blood 2015; 126 (08) 1017-1026
- 41 de Vos AF, Dessing MC, Lammers AJ. , et al. The polysaccharide capsule of Streptococcus pneumonia partially impedes MyD88-mediated immunity during pneumonia in mice. PLoS One 2015; 10 (02) e0118181
- 42 van Lieshout MHP, de Vos AF, Dessing MC. , et al. ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice. Eur J Immunol 2018; 48 (01) 66-79
- 43 McNeela EA, Burke A, Neill DR. , et al. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog 2010; 6 (11) e1001191
- 44 Fang R, Tsuchiya K, Kawamura I. , et al. Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection. J Immunol 2011; 187 (09) 4890-4899
- 45 Deppermann C, Kraft P, Volz J. , et al. Platelet secretion is crucial to prevent bleeding in the ischemic brain but not in the inflamed skin or lung in mice. Blood 2017; 129 (12) 1702-1706
- 46 Anderson R, Feldman C. Review manuscript: mechanisms of platelet activation by the pneumococcus and the role of platelets in community-acquired pneumonia. J Infect 2017; 75 (06) 473-485
- 47 Deppermann C, Kubes P. Platelets and infection. Semin Immunol 2016; 28 (06) 536-545
- 48 de Stoppelaar SF, Claushuis TA, Schaap MC. , et al. Toll-like receptor signalling is not involved in platelet response to Streptococcus pneumoniae in vitro or in vivo. PLoS One 2016; 11 (06) e0156977
- 49 Wagener BM, Hu PJ, Oh JY. , et al. Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: a preclinical experimental study. PLoS Med 2018; 15 (03) e1002522
- 50 Haining EJ, Cherpokova D, Wolf K. , et al. CLEC-2 contributes to hemostasis independently of classical hemITAM signaling in mice. Blood 2017; 130 (20) 2224-2228
- 51 Kreiniz N, Bejar J, Polliack A, Tadmor T. Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma. Hematol Oncol 2018; 36 (01) 349-354