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C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-6916-5490
Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
2010 (English)In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 215, no 12, 987-995 p.Article in journal (Refereed) Published
Abstract [en]

Blood platelets are emerging as important immunomodulatory cells, but complement interaction with platelets is not well understood. Several platelet structures have been described as complement protein 1q (C1q) binding receptors, such as C1qRp/CD93 and gC1qR. However, there are conflicting results whether these receptors are C1q binding structures, or even at all expressed on the cell surface. Recently, the collagen-binding integrin alphaIIbetaI was reported to bind C1q on mast cells, and this receptor is also present on platelets. The aim of this study was to further characterize the effects of C1q on platelets, by quantifying the platelet surface expression of P-selectin (CD62P) and monitoring the formation of platelet-neutrophil aggregates. Using flow cytometry, we found that C1q dose-dependently triggered a rapid but moderate and transient up-regulation of P-selectin already within 5s of C1q exposure. Pre-incubation with an antibody directed against gC1qR significantly inhibited (with 57% compared to control) the up-regulation, whereas an antibody towards the alphaIIbetaI-integrin showed no effect. Stimulation with C1q did not change the cytosolic calcium-levels, as measured with the fluorescent ratiometric probe Fura-2, however, a protein kinase C inhibitor (GF109203x) blocked the C1q-induced P-selectin expression. Furthermore, pre-incubation of platelets with C1q diminished both the collagen as well as the collagen-related peptide-induced up-regulation of P-selectin, most evident after 90s of stimulation. This indicates that C1q may regulate platelet activation via the GPVI receptor, which is a novel finding. Moreover, C1q antagonized the collagen-induced formation of platelet-neutrophil aggregates, indicating a reduced interaction between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1(PSGL-1/CD162). In summary, C1q induces a moderate rapid platelet P-selectin expression, modulates subsequent collagen and collagen-related peptide stimulation of platelets, and inhibits the formation of platelet-neutrophil aggregates. These immuno-regulatory effects of C1q may have a crucial role in innate immunity and inflammation.

Place, publisher, year, edition, pages
2010. Vol. 215, no 12, 987-995 p.
Keyword [en]
AlfaIIbetaI integrin (αIIβI, GpIa/IIa), Blood platelet, C1q, C1qR, Complement, Platelet–neutrophil aggregates, P-selectin (CD62 P)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-54665DOI: 10.1016/j.imbio.2009.11.004ISI: 000285532100007PubMedID: 20163886OAI: oai:DiVA.org:liu-54665DiVA: diva2:306619
Note
Original Publication: Caroline Skoglund, Jonas Wetterö, Pentti Tengvall and Torbjörn Bengtsson, C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets, 2010, Immunobiology, (215), 12, 987-995. http://dx.doi.org/10.1016/j.imbio.2009.11.004 Copyright: Elsevier Science B. V., Amsterdam http://www.elsevier.com/ Available from: 2010-03-30 Created: 2010-03-30 Last updated: 2017-12-12
In thesis
1. Platelets in inflammation: Role of complement protein C1q, C-reactive proteinand toll-like receptors
Open this publication in new window or tab >>Platelets in inflammation: Role of complement protein C1q, C-reactive proteinand toll-like receptors
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platelets are proven essential in haemostasis, however, they are now also increasingly recognized as cells with important immunomodulatory properties, e.g. through interaction with leukocytes and several species of bacteria and by release inflammatory mediators upon activation. Moreover, platelets express receptors involved in immunity and inflammation such as Fcγ‐receptor IIa, complement protein C1q‐receptors (gC1qR, cC1qR, CD93 and α2β1) and toll‐like receptors (TLR‐1, ‐2, ‐4, ‐6 and ‐9). C1q, C‐reactive protein (CRP) and TLRs are all pattern recognition molecules able to recognize non‐self structures and initiate an immune response. Uncontrolled or misdirected activation of platelets and the immune response is involved in the onset and progress of several conditions with an inflammatory component, such as coronary artery disease and autoimmune diseases.

Hence, the aims of the present thesis were to investigate the effects and q mechanisms of C1and CRP on platelet activation, and to clarify the intracellular signaling events provoked by TLR‐2 stimulation of platelets. Platelet interaction with immune complexes is poorly understood, however by utilizing well‐characterized model surfaces with adsorbed IgG and microscopy, we show that both C1q and CRP are able to inhibit FcγR‐mediated platelet adhesion and spreading. Using isolated platelets in suspension and flow cytometry, we also found that C1q triggers a rapid, moderate and transient up‐regulation of P‐selectin that is sensitive to blockade of gC1qR and protein kinase C (PKC), but not blockade of α2β1. Additionally, subsequent platelet activation by collagen or collagen‐related peptide (GPVI specific) is inhibited by C1q, suggesting a role for GPVI in C1q‐mediated regulation of collagen‐induced platelet activation. Whole blood studies revealed that C1q inhibits total cell aggregation, formation of platelet‐leukocyte aggregates, and potentiates the production of reactive oxygen species (ROS), all in a platelet‐dependent manner. Furthermore, using the TLR‐2/1 agonist Pam3CSK4 we found that TLR‐2/1‐activation of platelets is mediated via a P2X1‐dependent increase in intracellular free Ca2+, P2Y1 and P2Y12 –receptor ligation, and activation of cyclooxygenase. We also found that platelets express IRAK‐1, however, without being rapidly phosphorylated upon Pam3CSK4 stimulation and thus probably not involved in the early aggregation/secretion response. Furthermore, TLR‐2/6 stimulation does not lead to platelet activation but instead inhibits TLR‐2/1‐provoked activation. Taken together, these findings further strengthen the role of platelets as key players in inflammatory processes.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1176
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54667 (URN)978-91-7393-418-3 (ISBN)
Public defence
2010-04-16, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Supervisors
Available from: 2010-03-30 Created: 2010-03-30 Last updated: 2015-06-29Bibliographically approved

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Skoglund, CarolineWetterö, JonasTengvall, PenttiBengtsson, Torbjörn

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