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  • 1.
    Fälker, Knut
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine; Dept Clin & Expt Med, Linköping Univ, Linköping, Sweden.
    Klarström-Engström, Kristin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine.
    Lindahl, Tomas L.
    Dept Clin & Expt Med, Linköping Univ, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Biomedicine.
    The Toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLC gamma 2 signalling cascade2014In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 26, no 2, p. 279-286Article in journal (Refereed)
    Abstract [en]

    The specific TLR2/1 complex activator Pam3CSK4 has been shown to provoke prominent activation and aggregation of human non-nucleated platelets. As Pam3CSK4-evoked platelet activation does not employ the major signalling pathway established in nucleated immune cells, we investigated if the TLR2/1 complex on platelets may initiate signalling pathways known to be induced by physiological agonists such as collagen via GPVI or thrombin via PARs. We found that triggering TLR2/1 complex-signalling with Pam3CSK4, in common with that induced via GPVI, and in contrast to that provoked by PARS, involves tyrosine phosphorylation of the adaptor protein LAT as well as of PLC gamma 2 in a src- and Syk-dependent manner. In this respect, we provide evidence that Pam3CSK4 does not cross-activate GPVI. Further, by the use of platelets from a Glanzmann's thrombasthenia patient lacking beta(3), in contrast to findings in nucleated immune cells, we show that the initiation of platelet activation by Pam3CSK4 does not involve integrin beta(3) signalling; whereas the latter, subsequent to intermediate TXA2 synthesis and signalling, was found to be indispensable for proper dense granule secretion and full platelet aggregation. Together, our findings reveal that triggering the TLR2/1 complex with Pam3CSK4 initiates human platelet activation by engaging tyrosine kinases of the src family and Syk, the adaptor protein LAT, as well as the key mediator PLC gamma 2. (C) 2013 Elsevier Inc. All rights reserved.

  • 2.
    Klarström-Engström, Kristin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Platelets as immune cells in sensing bacterial infection2015Doctoral thesis, comprehensive summary (Other academic)
    List of papers
    1. Toll like receptor 2/1 mediated platelet adhesion and activation on bacterial mimetic surfaces is dependent on src/Syk-signaling and purinergic receptor P2X1 and P2Y12 activation
    Open this publication in new window or tab >>Toll like receptor 2/1 mediated platelet adhesion and activation on bacterial mimetic surfaces is dependent on src/Syk-signaling and purinergic receptor P2X1 and P2Y12 activation
    2014 (English)In: Biointerphases, ISSN 1934-8630, E-ISSN 1559-4106, Vol. 9, no 4, p. 041003-Article in journal (Refereed) Published
    Abstract [en]

    Platelets are considered to have important functions in inflammatory processes as key players in innate immunity. Toll like receptors (TLRs), expressed on platelets, recognize pathogen associated molecular patterns and trigger immune responses. Pathogens are able to adhere to human tissues and form biofilms which cause a continuous activation of the immune system. The authors aimed to investigate how immobilized Pam(3)CSK(4) (a synthetic TLR2/1 agonist) and IgG, respectively, resembling a bacterial focus, affects adhesion and activation of platelets including release of two cytokines, regulated on activation normal T-cell expressed and secreted (RANTES) and macrophage migration inhibitory factor (MIF). The authors also aim to clarify the signaling downstream of TLR2/1 and Fc gamma RII (IgG receptor) and the role of adenine nucleotides in this process. Biolayers of Pam(3)CSK(4) and IgG, respectively, were confirmed by null-ellipsometry and contact angle measurements. Platelets were preincubated with signaling inhibitors for scr and Syk and antagonists for P2X1 or P2Y1 [adenosine triphosphate (ATP), adenosine diphosphate (ADP) receptors] prior to addition to the surfaces. The authors show that platelets adhere and spread on both Pam(3)CSK(4)- and IgG-coated surfaces and that this process is antagonized by scr and Syc inhibitors as well as P2X1 and P2Y antagonists. This suggests that Pam(3)CSK(4) activated platelets utilize the same pathway as Fc gamma RII. Moreover, the authors show that ATP-ligation of P2X1 is of importance for further platelet activation after TLR2/1-activation, and that P2Y12 is the prominent ADP-receptor involved in adhesion and spreading. RANTES and MIF were secreted over time from platelets adhering to the coated surfaces, but no MIF was released upon stimulation with soluble Pam(3)CSK(4). These results clarify the importance of TLR2/1 and Fc gamma RII in platelet adhesion and activation, and strengthen the role of platelets as an active player in sensing bacterial infections.

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Cell Research
    Identifiers
    urn:nbn:se:oru:diva-42365 (URN)10.1116/1.4901135 (DOI)000347160900004 ()25553878 (PubMedID)
    Funder
    Swedish Heart Lung FoundationSwedish Society for Medical Research (SSMF)
    Note

    Funding Agencies:

    Swedish Medical Research Council

    Olle Engkvist Foundation

    Lars Hiertas Minne foundation

    Available from: 2015-02-04 Created: 2015-02-03 Last updated: 2017-12-05Bibliographically approved
    2. The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation
    Open this publication in new window or tab >>The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation
    2015 (English)In: Molecular Oral Microbiology, ISSN 2041-1006, E-ISSN 2041-1014, Vol. 30, no 1, p. 62-73Article in journal (Refereed) Published
    Abstract [en]

    Platelets are considered to have important functions in inflammatory processes and as actors in the innate immunity. Several studies have shown associations between cardiovascular disease and periodontitis, where the oral anaerobic pathogen Porphyromonas gingivalis has a prominent role in modulating the immune response. Porphyromonas gingivalis has been found in atherosclerotic plaques, indicating spreading of the pathogen via the circulation, with an ability to interact with and activate platelets via e.g. Toll-like receptors (TLR) and protease-activated receptors. We aimed to evaluate how the cysteine proteases, gingipains, of P.gingivalis affect platelets in terms of activation and chemokine secretion, and to further investigate the mechanisms of platelet-bacteria interaction. This study shows that primary features of platelet activation, i.e. changes in intracellular free calcium and aggregation, are affected by P.gingivalis and that arg-gingipains are of great importance for the ability of the bacterium to activate platelets. The P.gingivalis induced a release of the chemokine RANTES, however, to a much lower extent compared with the TLR2/1-agonist Pam(3)CSK(4), which evoked a time-dependent release of the chemokine. Interestingly, the TLR2/1-evoked response was abolished by a following addition of viable P.gingivalis wild-types and gingipain mutants, showing that both Rgp and Kgp cleave the secreted chemokine. We also demonstrate that Pam(3)CSK(4)-stimulated platelets release migration inhibitory factor and plasminogen activator inhibitor-1, and that also these responses were antagonized by P.gingivalis. These results supports immune-modulatory activities of P.gingivalis and further clarify platelets as active players in innate immunity and in sensing bacterial infections, and as target cells in inflammatory reactions induced by P.gingivalis infection.

    Keywords
    gingipains, migration inhibitory factor, periodontitis, platelets, Porphyromonas gingivalis, RANTES
    National Category
    Microbiology in the medical area Medical and Health Sciences
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:oru:diva-42616 (URN)10.1111/omi.12067 (DOI)000347897100006 ()25043711 (PubMedID)2-s2.0-84920994869 (Scopus ID)
    Funder
    Swedish Heart Lung FoundationSwedish Research Council
    Note

    Funding Agency:

    Foundation of Olle Engkvist

    Available from: 2015-02-13 Created: 2015-02-13 Last updated: 2018-01-11Bibliographically approved
    3. The platelet response to various strains of Porphyromonas gingivalis
    Open this publication in new window or tab >>The platelet response to various strains of Porphyromonas gingivalis
    (English)Manuscript (preprint) (Other academic)
    National Category
    Microbiology in the medical area
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:oru:diva-43013 (URN)
    Available from: 2015-02-27 Created: 2015-02-27 Last updated: 2018-01-11Bibliographically approved
    4. Porphyromonas gingivalis-induced lipid peroxidation: the role of platelets, gingipains and periodontal status.
    Open this publication in new window or tab >>Porphyromonas gingivalis-induced lipid peroxidation: the role of platelets, gingipains and periodontal status.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-43014 (URN)
    Available from: 2015-02-27 Created: 2015-02-27 Last updated: 2018-01-11Bibliographically approved
  • 3.
    Klarström-Engström, Kristin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    The platelet response to various strains of Porphyromonas gingivalisManuscript (preprint) (Other academic)
  • 4.
    Klarström-Engström, Kristin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brommesson, Caroline
    Department of Physics, Chemistry and Biology, Division of Molecular Surface Physics and Nanoscience, Linköping University, Linköping, Sweden.
    Kälvegren, Hanna
    Department of Clinical Pathology and Clinical Genetics, Linköping University Hospital, Linköping, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden .
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Toll like receptor 2/1 mediated platelet adhesion and activation on bacterial mimetic surfaces is dependent on src/Syk-signaling and purinergic receptor P2X1 and P2Y12 activation2014In: Biointerphases, ISSN 1934-8630, E-ISSN 1559-4106, Vol. 9, no 4, p. 041003-Article in journal (Refereed)
    Abstract [en]

    Platelets are considered to have important functions in inflammatory processes as key players in innate immunity. Toll like receptors (TLRs), expressed on platelets, recognize pathogen associated molecular patterns and trigger immune responses. Pathogens are able to adhere to human tissues and form biofilms which cause a continuous activation of the immune system. The authors aimed to investigate how immobilized Pam(3)CSK(4) (a synthetic TLR2/1 agonist) and IgG, respectively, resembling a bacterial focus, affects adhesion and activation of platelets including release of two cytokines, regulated on activation normal T-cell expressed and secreted (RANTES) and macrophage migration inhibitory factor (MIF). The authors also aim to clarify the signaling downstream of TLR2/1 and Fc gamma RII (IgG receptor) and the role of adenine nucleotides in this process. Biolayers of Pam(3)CSK(4) and IgG, respectively, were confirmed by null-ellipsometry and contact angle measurements. Platelets were preincubated with signaling inhibitors for scr and Syk and antagonists for P2X1 or P2Y1 [adenosine triphosphate (ATP), adenosine diphosphate (ADP) receptors] prior to addition to the surfaces. The authors show that platelets adhere and spread on both Pam(3)CSK(4)- and IgG-coated surfaces and that this process is antagonized by scr and Syc inhibitors as well as P2X1 and P2Y antagonists. This suggests that Pam(3)CSK(4) activated platelets utilize the same pathway as Fc gamma RII. Moreover, the authors show that ATP-ligation of P2X1 is of importance for further platelet activation after TLR2/1-activation, and that P2Y12 is the prominent ADP-receptor involved in adhesion and spreading. RANTES and MIF were secreted over time from platelets adhering to the coated surfaces, but no MIF was released upon stimulation with soluble Pam(3)CSK(4). These results clarify the importance of TLR2/1 and Fc gamma RII in platelet adhesion and activation, and strengthen the role of platelets as an active player in sensing bacterial infections.

  • 5.
    Klarström-Engström, Kristin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kälvegren, H.
    Department of Clinical Pathology and Clinical Genetics, Linköping University Hospital, Linköping, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation2015In: Molecular Oral Microbiology, ISSN 2041-1006, E-ISSN 2041-1014, Vol. 30, no 1, p. 62-73Article in journal (Refereed)
    Abstract [en]

    Platelets are considered to have important functions in inflammatory processes and as actors in the innate immunity. Several studies have shown associations between cardiovascular disease and periodontitis, where the oral anaerobic pathogen Porphyromonas gingivalis has a prominent role in modulating the immune response. Porphyromonas gingivalis has been found in atherosclerotic plaques, indicating spreading of the pathogen via the circulation, with an ability to interact with and activate platelets via e.g. Toll-like receptors (TLR) and protease-activated receptors. We aimed to evaluate how the cysteine proteases, gingipains, of P.gingivalis affect platelets in terms of activation and chemokine secretion, and to further investigate the mechanisms of platelet-bacteria interaction. This study shows that primary features of platelet activation, i.e. changes in intracellular free calcium and aggregation, are affected by P.gingivalis and that arg-gingipains are of great importance for the ability of the bacterium to activate platelets. The P.gingivalis induced a release of the chemokine RANTES, however, to a much lower extent compared with the TLR2/1-agonist Pam(3)CSK(4), which evoked a time-dependent release of the chemokine. Interestingly, the TLR2/1-evoked response was abolished by a following addition of viable P.gingivalis wild-types and gingipain mutants, showing that both Rgp and Kgp cleave the secreted chemokine. We also demonstrate that Pam(3)CSK(4)-stimulated platelets release migration inhibitory factor and plasminogen activator inhibitor-1, and that also these responses were antagonized by P.gingivalis. These results supports immune-modulatory activities of P.gingivalis and further clarify platelets as active players in innate immunity and in sensing bacterial infections, and as target cells in inflammatory reactions induced by P.gingivalis infection.

  • 6.
    Klarström-Engström, Kristin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnusson, A.
    Demirel, I.
    Lönn, J.
    Starkhammar Johansson, C.
    Kälvegren, Hanna
    Department of Clinical Pathology and Clinical Genetics, Linköping University Hospital, Linköping, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden .
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Porphyromonas gingivalis-induced lipid peroxidation: the role of platelets, gingipains and periodontal status.Manuscript (preprint) (Other academic)
  • 7.
    Klarström-Engström, Kristin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Skoglund, C.
    Linköping University, Linköping, Sweden.
    Kälvegren, Hanna
    Linköping University Hospital, Linköping, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    The role of platelets in inflammation at sites of infection: toll like receptor 2/1 mediated platelet adhesion on bacterial peptide-mimetic surfaces2012In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 93, p. S8-S8Article in journal (Other academic)
  • 8.
    Klarström-Engström, Kristin
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Clinical trial unit.
    Zhang, Boxi
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Human renal fibroblasts are strong immunomobilizers during a urinary tract infection mediated by uropathogenic Escherichia coli2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, no 1, article id 2296Article in journal (Refereed)
    Abstract [en]

    To prevent the onset of urosepsis and reduce mortality, a better understanding of how uropathogenic Escherichia coli (UPEC) manages to infiltrate the bloodstream through the kidneys is needed. The present study elucidates if human renal interstitial fibroblasts are part of the immune response limiting a UPEC infection, or if UPEC has the ability to modulate the fibroblasts for their own gain. Microarray results showed that upregulated genes were associated with an activated immune response. We also found that chemokines released from renal fibroblasts upon a UPEC infection could be mediated by LPS and triacylated lipoproteins activating the TLR2/1, TLR4, MAPK, NF-κB and PKC signaling pathways. Furthermore, UPEC was also shown to be able to adhere and invade renal fibroblasts, mediated by the P-fimbriae. Furthermore, it was found that renal fibroblasts were more immunoreactive than renal epithelial cells upon a UPEC infection. However, both renal fibroblasts and epithelial cells were equally efficient at inducing neutrophil migration. In conclusion, we have found that human renal fibroblasts can sense UPEC and mobilize a host response with neutrophil migration. This suggests that renal fibroblasts are not only structural cells that produce and regulate the extracellular matrix, but also highly immunoreactive cells.

  • 9.
    Lönn, J.
    et al.
    Department of Oral Biology, Institute of Odontology, Malmö University, Malmö, Sweden; PEAS Institute AB, Linköping, Sweden.
    Ljunggren, S.
    Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine Center, Linköping University, Linköping, Sweden.
    Klarström-Engström, Kristin
    Department of Medical Sciences, Örebro University, Örebro, Sweden.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Karlsson, H.
    Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine Center, Linköping University, Linköping, Sweden.
    Lipoprotein modifications by gingipains of Porphyromonas gingivalis2018In: Journal of Periodontal Research, ISSN 0022-3484, E-ISSN 1600-0765, Vol. 53, no 3, p. 403-413Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Several studies have shown an association between periodontitis and cardiovascular disease (CVD). Atherosclerosis is the major cause of CVD, and a key event in the development of atherosclerosis is accumulation of lipoproteins within the arterial wall. Bacteria are the primary etiologic agents in periodontitis and Porphyromonas gingivalis is the major pathogen in the disease. Several studies support a role of modified low-density lipoprotein (LDL) in atherogenesis; however, the pathogenic stimuli that induce the changes and the mechanisms by which this occur are unknown. This study aims to identify alterations in plasma lipoproteins induced by the periodontopathic species of bacterium, P. gingivalis, in vitro.

    MATERIAL AND METHODS: Plasma lipoproteins were isolated from whole blood treated with wild-type and gingipain-mutant (lacking either the Rgp- or Kgp gingipains) P. gingivalis by density/gradient-ultracentrifugation and were studied using 2-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization mass spectrometry. Porphyromonas gingivalis-induced lipid peroxidation and antioxidant levels were measured by thiobarbituric acid-reactive substances and antioxidant assay kits, respectively, and lumiaggregometry was used for measurement of reactive oxygen species (ROS) and aggregation.

    RESULTS: Porphyromonas gingivalis exerted substantial proteolytic effects on the lipoproteins. The Rgp gingipains were responsible for producing 2 apoE fragments, as well as 2 apoB-100 fragments, in LDL, and the Kgp gingipain produced an unidentified fragment in high-density lipoproteins. Porphyromonas gingivalis and its different gingipain variants induced ROS and consumed antioxidants. Both the Rgp and Kgp gingipains were involved in inducing lipid peroxidation.

    CONCLUSIONS: Porphyromonas gingivalis has the potential to change the expression of lipoproteins in blood, which may represent a crucial link between periodontitis and CVD.

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