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Kälvegren, Hanna
Publications (10 of 14) Show all publications
Klarstrom Engstrom, K., Khalaf, H., Kälvegren, H. & Bengtsson, T. (2015). The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation. Molecular Oral Microbiology, 30(1), 62-73
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.

Place, publisher, year, edition, pages
Wiley: 12 months, 2015
Keywords
gingipains; migration inhibitory factor; periodontitis; platelets; Porphyromonas gingivalis; RANTES
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114235 (URN)10.1111/omi.12067 (DOI)000347897100006 ()25043711 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Heart-Lung foundation; Foundation of Olle Engkvist

Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2017-12-04
Klarstrom Engstrom, K., Skoglund, C., Kälvegren, H. & Bengtsson, T. (2014). 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. BIOINTERPHASES, 9(4), 041003
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, 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. (C) 2014 American Vacuum Society.

Place, publisher, year, edition, pages
American Vacuum Society / SpringerOpen / Springer Verlag (Germany) / AVS: Science and Technology of Materials, Interfaces and Processing, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113782 (URN)10.1116/1.4901135 (DOI)000347160900004 ()25553878 (PubMedID)
Note

Funding Agencies|Swedish Heart-Lung Foundation; Swedish Medical Research Council; Olle Engkvist Foundation; Lars Hiertas Minne foundation; Swedish Society for Medical Research (SSMF)

Available from: 2015-02-02 Created: 2015-01-30 Last updated: 2015-02-09
Lönn, J., Starkhammar Johansson, C., Kälvegren, H., Brudin, L., Skoglund, C., Garvin, P., . . . Nayeri, F. (2012). Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition. Results in Immunology, 2, 7-12
Open this publication in new window or tab >>Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition
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2012 (English)In: Results in Immunology, ISSN 2211-2839, Vol. 2, p. 7-12Article in journal (Refereed) Published
Abstract [en]

Hepatocyte growth factor (HGF) is an angiogenic, cardioprotective factor important for tissue and vascular repair. High levels of HGF are associated with chronic inflammatory diseases, such as coronary artery disease (CAD) and periodontitis, and are suggested as a marker of the ongoing atherosclerotic event in patients with CAD. Periodontal disease is more prevalent among patients with CAD than among healthy people. Recent studies indicate a reduced biological activity of HGF in different chronic inflammatory conditions. Biologically active HGF has high affinity to heparan sulfate proteoglycan (HSPG) on cell-membrane and extracellular matrix. The aim of the study was to investigate the serum concentration and the biological activity of HGF with ELISA and surface plasmon resonance (SPR), respectively, before and at various time points after percutaneous coronary intervention (PCI) in patients with CAD, and to examine the relationship with periodontal condition. The periodontal status of the CAD patients was examined, and the presence of P. gingivalis in periodontal pockets was analyzed with PCR. The HGF concentration was significantly higher, at all time-points, in patients with CAD compared to the age-matched controls (P< 0.001), but was independent of periodontal status. The HGF concentration and the affinity to HSPG adversely fluctuated over time, and the biological activity increased one month after intervention in patients without periodontitis. We conclude that elevated concentration of HGF but with reduced biological activity might indicate a chronic inflammatory profile in patients with CAD and periodontitis.

Place, publisher, year, edition, pages
Elsevier, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86207 (URN)10.1016/j.rinim.2011.12.002 (DOI)
Available from: 2012-12-11 Created: 2012-12-11 Last updated: 2014-09-10
Engstrom Klarstrom, K., Skoglund, C., Kälvegren, H. & Bengtsson, T. (2012). The role of platelets in inflammation at sites of infection; toll like receptor 2/1 mediated platelet adhesion on bacterial peptide-mimetic surfaces in CARDIOVASCULAR RESEARCH, vol 93, issue , pp S8-S8. In: CARDIOVASCULAR RESEARCH (pp. S8-S8). Oxford University Press (OUP): Policy B, 93
Open this publication in new window or tab >>The role of platelets in inflammation at sites of infection; toll like receptor 2/1 mediated platelet adhesion on bacterial peptide-mimetic surfaces in CARDIOVASCULAR RESEARCH, vol 93, issue , pp S8-S8
2012 (English)In: CARDIOVASCULAR RESEARCH, Oxford University Press (OUP): Policy B , 2012, Vol. 93, p. S8-S8Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy B, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76810 (URN)000301975800017 ()
Available from: 2012-04-20 Created: 2012-04-20 Last updated: 2012-04-20
Jönsson, S., Lundberg, A., Kälvegren, H., Bergström, I., Szymanowski, A. & Jonasson, L. (2011). Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris. PLOS ONE, 6(4)
Open this publication in new window or tab >>Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris
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2011 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 4Article in journal (Refereed) Published
Abstract [en]

Objective: There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA). Methods: In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR. Results: Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p andlt; 0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p andlt; 0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p andlt; 0.01. Conclusion: Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that the leukocytes are more prone to release and produce MMP-9 in symptomatic and angiographically verified CAD-a phenomenon that may have clinical implications in the course of disease.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68212 (URN)10.1371/journal.pone.0019340 (DOI)000290024700142 ()
Note
Original Publication: Simon Jönsson, Anna Lundberg, Hanna Kälvegren, Ida Bergström, Aleksander Szymanowski and Lena Jonasson, Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris, 2011, PLOS ONE, (6), 4. http://dx.doi.org/10.1371/journal.pone.0019340 Licensee: Public Library of Science (PLoS) http://www.plos.org/Available from: 2011-05-13 Created: 2011-05-13 Last updated: 2015-02-18
Kälvegren, H., Jonsson, S. & Jonasson, L. (2011). Release of matrix metalloproteinases-1 and-2, but not-9, from activated platelets measured by enzyme-linked immunosorbent assay. Platelets, 22(8), 572-578
Open this publication in new window or tab >>Release of matrix metalloproteinases-1 and-2, but not-9, from activated platelets measured by enzyme-linked immunosorbent assay
2011 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 8, p. 572-578Article in journal (Refereed) Published
Abstract [en]

Matrix metalloproteinases (MMPs), in particular MMP-9, have been introduced as novel biomarkers in coronary artery disease. Activated platelets are considered to be a major source of the highly elevated levels of MMPs that are detected in serum compared to plasma. The aim of this study was to clarify if activated platelets release MMPs-1, -2 and -9 as measured by enzyme-linked immunosorbent assays (ELISA). Isolated platelets (separated by several procedures) or platelet-rich plasma (PRP) were stimulated by collagen, thrombin or the TLR2 agonist Pam(3)CSK(4). The concentrations of MMPs-1,-2 and -9 in supernatants were determined by ELISA. In addition, a MMP-9 enzyme activity assay was used as well as immunofluorescent staining of MMPs-1,-2 and 9 in platelets. Isolated platelets stimulated by collagen, thrombin or Pam(3)CSK(4) released significant amounts of MMP-1 to the supernatant measured as either pro- or total-MMP-1. However, there was no detectable release of MMP-2 or -9 from isolated platelets. Collagen-stimulated platelets in PRP released MMP-2, but not -9. Before stimulation; platelets were positive for MMPs-1 and -2, but not -9, as assessed by immunofluorescence. Acting as positive controls, neutrophils were found to release significant amounts of MMP-9. Our findings indicate that activated platelets may be a major source of MMP-1 and to a minor extent MMP-2, in peripheral blood. However, in contrast to what has been argued in previous literature, platelets appear to be only negligible contributors to circulating MMP-9.

Place, publisher, year, edition, pages
Informa Healthcare, 2011
Keywords
Matrix metalloproteinase, platelets
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72150 (URN)10.3109/09537104.2011.583300 (DOI)000296504400003 ()
Available from: 2011-11-18 Created: 2011-11-18 Last updated: 2017-12-08
Jönsson, S., Kälvegren, H., Lundberg, A. & Jonasson, L. (2010). Neutrophils but not platelets are a major source of MMP-9 in coronary artery disease in EUROPEAN HEART JOURNAL, vol 31, issue , pp 486-487. In: EUROPEAN HEART JOURNAL (pp. 486-487). Oxford University Press, 31
Open this publication in new window or tab >>Neutrophils but not platelets are a major source of MMP-9 in coronary artery disease in EUROPEAN HEART JOURNAL, vol 31, issue , pp 486-487
2010 (English)In: EUROPEAN HEART JOURNAL, Oxford University Press , 2010, Vol. 31, p. 486-487Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Oxford University Press, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67383 (URN)000281531903149 ()
Available from: 2011-04-11 Created: 2011-04-11 Last updated: 2011-04-21
Kälvegren, H., Fridfeldt, J. & Bengtsson, T. (2010). The role of plasma adenosine deaminase in chemoattractant-stimulated oxygen radical production in neutrophils. EUROPEAN JOURNAL OF CELL BIOLOGY, 89(6), 462-467
Open this publication in new window or tab >>The role of plasma adenosine deaminase in chemoattractant-stimulated oxygen radical production in neutrophils
2010 (English)In: EUROPEAN JOURNAL OF CELL BIOLOGY, ISSN 0171-9335, Vol. 89, no 6, p. 462-467Article in journal (Refereed) Published
Abstract [en]

Objectives: Adenosine deaminase (ADA) has a role in many immunity mediated disorders, such as asthma, tuberculosis and coronary artery disease. This study aims to investigate the ability of plasma ADA to modulate reactive oxygen species (ROS) production in neutrophils, and examine the involvement of adenosine and the cyclic AMP signaling pathway in this process. Methods: Neutrophils were stimulated, in the absence or presence of plasma, with the chemotactic peptide fMLP (formyl-methionyl-leucyl-phenylalanine), and the ROS production was determined with luminol-enhanced chemiluminescence. Activity of ADA was measured spectrophotometrically. Results: Plasma dose-dependently amplified the ROS generation in fMLP-stimulated neutrophils. In parallel, incubation of neutrophils in plasma elevated the total ADA-activity approximately 10 times from 1.3 U/ml to 12 U/ml. Inhibition of ADA, or type IV phosphodiesterases, significantly lowered the plasma-mediated ROS production. Furthermore, the high-affinity adenosine A(1) receptor antagonists DPCPX and 8-phenyltheophylline markedly inhibited the plasma-induced respiratory burst in neutrophils, suggesting an AI receptor-mediated mechanism. Conclusions: This study suggests that plasma ADA amplifies the release of toxic oxygen radicals from neutrophils through a downregulation of the inhibitory adenosine/cAMP-system and an enhanced activation of the stimulatory adenosine A(1)-receptor. This mechanism has probably a crucial role in regulating neutrophil function and in the defence against microbial infections. However, a sustained neutrophil activation could also contribute to inflammatory disorders such as atherosclerosis.

Place, publisher, year, edition, pages
Elsevier Science B. V., Amsterdam, 2010
Keywords
Leukocyte, Reactive oxygen species, Adenosine deaminase, Plasma, Phosphodiesterase, Inflammation, Adenosine A1 receptor antagonist
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-57157 (URN)10.1016/j.ejcb.2009.12.004 (DOI)000277688100005 ()
Available from: 2010-06-11 Created: 2010-06-11 Last updated: 2014-01-15Bibliographically approved
Kälvegren, H., Skoglund, C., Helldahl, C., Lerm, M., Grenegård, M. & Bengtsson, T. (2010). Toll-like receptor 2 stimulation of platelets is mediated by purinergic P2X1-dependent Ca2+ mobilisation, cyclooxygenase and purinergic P2Y1 and P2Y12 receptor activation. Thrombosis and Haemostasis, 103(2), 398-407
Open this publication in new window or tab >>Toll-like receptor 2 stimulation of platelets is mediated by purinergic P2X1-dependent Ca2+ mobilisation, cyclooxygenase and purinergic P2Y1 and P2Y12 receptor activation
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2010 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 103, no 2, p. 398-407Article in journal (Refereed) Published
Abstract [en]

Toll-like receptor 2 (TLR2), which recognise and respond to conserved microbial pathogen-associated molecular patterns, is expressed on the platelet surface. Furthermore, it has recently been shown that the TLR2/1 agonist Pam(3)CSK(4) stimulates platelet activation. The aim of the present study was to clarify important signalling events in Pam(3)CSK(4)-induced platelet aggregation and secretion. Platelet interaction with Pam(3)CSK(4) and the TLR2/6 agonist MALP-2 was studied by analysing aggregation, ATP-secretion, [Ca2+](i) mobilisation and thromboxane B2 (TxB(2)) production. The results show that Pam(3)CSK(4) but not MALP-2 induces [Ca2+](i) increase, TxB(2) production, dense granule secretion and platelet aggregation. Preincubation of platelets with MALP-2 inhibited the Pam(3)CSK(4)-induced responses. The ATP-secretion and aggregation in Pam(3)CSK(4)-stimulated platelets was impeded by the purinergic P2X(1) inhibitor MRS 2159, the purinergic P2Y(1) and P2Y(12) antagonists MRS 2179 and cangrelor, the phospholipase C inhibitor U73122, the calcium chelator BAPT-AM and aspirin. The calcium mobilisation was lowered by MRS 2159, aspirin and U73122 whereas the TxB(2) production was antagonised by MRS 2159, aspirin and BAPT-AM. When investigating the involvement of the myeloid differentiation factor-88 (MyD88) -dependent pathway, we found that platelets express MyD88 and interleukin 1 receptor-associated kinase (IRAK-1), which are proteins important in TLR signalling. However, Pam(3)CSK(4) did not stimulate a rapid (within 10 minutes) phosphorylation of IRAK-1 in platelets. In conclusion, the results show that Pam(3)CSK(4)-induced platelet aggregation and secretion depends on a P2X(1)-mediated Ca2+ mobilisation, production of TxA(2) and ADP receptor activation. The findings in this study further support a role for platelets in sensing bacterial components.

Keywords
Infection, purinergic P2X(1) receptor, atherosclerosis, MALP-2, Pam(3)CSK(4), platelet, MyD88, IRAK-1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54249 (URN)10.1160/TH09-07-0442 (DOI)000274734100022 ()
Available from: 2010-03-05 Created: 2010-03-05 Last updated: 2017-12-12Bibliographically approved
Kälvegren, H., Fridfeldt (Berggren), J., Garvin, P., Wind, L., Leanderson, P., Kristenson, M., . . . Richter, A. (2008). Correlation between rises in Chlamydia pneumoniae-specific antibodies, platelet activation and lipid peroxidation after percutaneous coronary intervention.. European Journal of Clinical Microbiology and Infectious Diseases, 27(7), 503-511
Open this publication in new window or tab >>Correlation between rises in Chlamydia pneumoniae-specific antibodies, platelet activation and lipid peroxidation after percutaneous coronary intervention.
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2008 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 27, no 7, p. 503-511Article in journal (Refereed) Published
Abstract [en]

We recently showed that Chlamydia pneumoniae activates platelets in vitro, with an associated oxidation of low-density lipoproteins. The aim of this study was to investigate whether C. pneumoniae is released during percutaneous coronary intervention (PCI) and, thereby, causes platelet activation and lipid peroxidation. Seventy-three patients undergoing coronary angiography and following PCI or coronary artery bypass graft (CABG) and 57 controls were included in the study. C. pneumoniae antibodies, serotonin and lipid peroxidation were measured before and 24 h, 1 month and 6 months after angiography. The results show that serum C. pneumoniae IgA concentrations were significantly higher in patients than in the controls. Furthermore, in 38% of the C. pneumoniae IgG positive patients, the C. pneumoniae IgG concentration increased 1 month after PCI. The levels of C. pneumoniae IgG antibodies 1 month after PCI correlated with plasma-lipid peroxidation (r = 0.91, P < 0.0001) and platelet-derived serotonin (r = 0.62, P = 0.02). There was no elevation in the total serum IgG 1 month after PCI. In conclusion, the present results suggest that PCI treatment of coronary stenosis releases C. pneumoniae from the atherosclerotic lesions, which leads to platelet activation and lipid peroxidation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14388 (URN)10.1007/s10096-008-0465-y (DOI)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-13Bibliographically approved
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