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C1q regulates collagendependentproduction of reactive oxygen species, formation of plateletleukocyteaggregates and levels of soluble Pselectinin whole blood
Linköping University, Department of Medicine 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 Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
2010 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

Blood platelets are nowadays recognized as cells with immuno‐modulatory properties as they express receptors involved in immunity (e.g. complement‐, toll‐like‐ and Fcγ‐receptors) and release inflammatory mediators. Furthermore, formation of plateletleukocyte aggregates has an important role during inflammatory conditions, e.g. coronary artery disease. We have previously reported regulatory effects of complement protein 1q (C1q) on platelet activation in experimental setups using isolated cells. In the present study we have continued by investigating the effect of C1q on collagen‐induced aggregation and production of reactive oxygen species (ROS), formation of plateletleukocyte aggregates and levels of soluble P‐selectin in whole blood. Impedance measurements showed that C1q, at physiological concentrations, inhibited collageninduced aggregation in whole blood, whereas it potentiated the collagen‐provoked production of ROS in a luminal‐dependent chemiluminescence assay. The potentiation was dependent on platelets, as the effect was not seen when the platelet fibrinogen binding receptor GpIIb/IIIa was blocked by Reopro. Moreover, the formation of large platelet‐leukocyte aggregates in collagen‐stimulated whole blood was inhibited by C1q. This may be explained by the finding that C1q antagonized the collagen‐induced activation, revealed by lowered levels of soluble P‐selectin. In conclusion, C1q may have an important role in regulating platelet activation and associated leukocyte recruitment during vessel wall injury and thus be involved in inflammatory disorders such as coronary artery disease.

Place, publisher, year, edition, pages
2010. Vol. 215, 987-995 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-54666OAI: oai:DiVA.org:liu-54666DiVA: diva2:306623
Available from: 2010-03-30 Created: 2010-03-30 Last updated: 2015-06-29
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)
Opponent
Supervisors
Available from: 2010-03-30 Created: 2010-03-30 Last updated: 2015-06-29Bibliographically approved

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Skoglund, CarolineWetterö, JonasBengtsson, Torbjörn

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