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Platelet-mediated inhibition of polymorphonuclear neutrophil apoptosis principally involves membranes structures: role of sialyl-Lewisχ epitopes and CD18
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective and design: To clarify the long-time effects of platelets on polymorphonuclear neutrophils (PMNs) apoptosis, with particular emphasis on the involvement of cell adhesion molecules (CAMs).

Material: Isolated human platelets and PMNs.

Treatment: PMNs were treated with antibodies towards adhesion molecules CD18 (2 µg/ml), sialyl-Lewisχ (2 µg/ml) or P-selectin glycoprotein ligand 1 (5 µg/ml) and then incubated in the absence or presence of resting, thrombin-activated or inhibited platelets (PMN:platelet ratio of 1:50), platelet membrane (0.7 mg/ml; equivalent to the 1:50 ratio), or supematant from thrombin-activated platelets.

Methods: Measurement of DNA fragmentation using flow cytometry, microscopical evaluation of adhesion and cell death. Light transmission analysis for recording platelet aggregation.

Results: Activated, and to lesser extent, resting platelets prevented spontaneous PMN apoptosis. Comparable effects were detected by using platelet membrane. Platelet-mediated suppression of PMN apoptosis and PMN-platelet adhesion were reversed by pretreatment with antibodies directed towards the adhesive structures sialyl-Lewisχ (p<0.001).

Conclusions: Our results point to a central role of CAMs in plateletinduced inhibition of PMN apoptosis. Furthermore, the results add new evidences for a close association between the hemostatic and the inflammatory systems.

National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-84797OAI: diva2:561913
Available from: 2012-10-22 Created: 2012-10-22 Last updated: 2012-10-22Bibliographically approved
In thesis
1. Platelet-mediated inhibition of polymorphonuclear neutrophil apoptosis
Open this publication in new window or tab >>Platelet-mediated inhibition of polymorphonuclear neutrophil apoptosis
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neutrophils play an important role in the cell-mediated immune response against invading micro-organisms. Upon infection, neutrophils in the bloodstream transmigrate into the tissue where they bind to and engulf the microbes. The infecting agent is then eliminated using reactive oxygen species (ROS) and proteolytic enzymes. It is crucial that the life span of activated neutrophils is tightly regulated since the prolonged release of ROS can cause severe damage to the surrounding tissue. Therefore, programmed cell suicide through apoptosis, and the subsequent ingestion of apoptotic neutrophils by neighbouring cells, are essential to the rapid resolution of inflammation.

For the apoptotic process to work according to plan, an extensive control system is at work, instructing the neutrophil when and where to die. This system is influenced by intracellular as well as extracellular signals, that are conveyed through the neutrophil plasma membrane by cell adhesion molecules, for example integrins. The aim of this thesis was to investigate the involvement of adhesion molecules in the regulation of the neutrophil ROS production and apoptosis. We found that when neutrophils were challenged with particles exposing antibodies towards ß2-integrins they produced intracellular ROS, and this was dependent on reorganisation of the cytoskeleton. The particles also induced caspase-independent neutrophil apoptosis, and this ß2-integrin mediated signalling seemed to occur independently of tyrosine phosphorylation.

Interaction of neutrophils with a potential biomaterial, a titanium-peroxy gel, reversibly inhibited ROS production and decreased spontaneous apoptosis. This effect was contact-dependent but involved cell signalling via adhesion molecules other than ß2-integrins. We also showed that platelet-induced inhibition of neutrophil apoptosis involved both ß2-integrins and carbohydrate structures, and that activated platelets were more efficient than resting platelets. Platelet membranes also inhibited neutrophil apoptosis, supporting the notion of adhesion molecule involvement.

In conclusion, this thesis shows that adhesion molecules are involved in the regulation of neutrophil ROS production and apoptosis. Adhesion molecule signalling pathways may therefore be potential new therapeutic targets for treatment of diseases involving acute inflammation.

Abstract [sv]

Neutrafiler spelar en viktig roii i kroppens cellmedierade immunförsvar mot invaderande mikroorganismer. Vid en infektion vandrar neutrafilerna från blodet ut i vävnaden där de binder till och äter upp mikroberna. Dessa elimineras sedan med hjälp av reaktiva syremetaboliter och nedbrytande enzymer. Det är viktigt att livslängden för aktiverade neutrofiler kontrolleras noga eftersom långvarig frisättning av reaktiva syremetaboliter kan orsaka allvarliga skador på den omgivande vävnaden. Därför är programmerat självmord genom apoptos, och det faktum att apoptotiska neutrafiler äts upp av kringliggande celler, så viktigt för att en inflammation ska läka ut.

För att apoptosprocessen ska fungera som det är tänkt krävs ett omfattande kontrollsystem som talar om för neutrafilen när och var den ska dö. Systemet påverkas av både intra- och extracellulära signaler som överförs geno:ni neutrafilens plasamamembran av adhesionsmolekyler, tex integriner. Syftet med den här avhandlingen var att undersöka betydelsen av adhesionmolekyler i regleringen av neutrafilers apoptos och produktion av reaktiva syremetaboliter. Vi fann att när neutrafiler interagerade med partiklar som exponerar antikroppar mot ß2-integriner så producerade de reaktiva syremetaboliter intracellulärt. Denna signalväg krävde omlagringar i cytoskelettet. Partiklarna inducerade också caspasoberoende apoptos i neutrafilerna och denna ß2-integrin medierade signalering tycktes ske oberoende av tyrosinfosforylering.

Interaktion mellan neutrafiler och ett potentiellt biomaterial, en titanperoxidgel, gav en reversibel hämning av produktionen av reaktiva syrernetaboliter och minskad spontanapoptas. Effekten var kontaktberoende men signalerna gick via andra adhesionsmolekyler än ß2-integriner. Vi såg också att trombocytmedieract hämning av neutrofilapoptos involverade både ß2-integriner och kolhydratstrukturer, och att aktiverade trombocyter var effektivare än vilande trombocyter. Membran från trombocyter hämmade också neutrofilapoptos vilket stöder iden om att adhesionsmolekyler är inblandade.

Sammanfattningsvis visar den här avhandlingen att adhesions-molekyler är inblandade i regleringen av neutrafilers apoptos och produktion av reaktiva syremetaboliter. De signalvägar som används av adhesionsmolekylerna skulle därmed kunna utgöra nya mål för mediciner som används vid sjukdomar där akut inflammation är inblandad.

Place, publisher, year, edition, pages
Linköping: Linköping Universitet, 2004. 70 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 833
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-23981 (URN)3532 (Local ID)91-7373-805-0 (ISBN)3532 (Archive number)3532 (OAI)
Public defence
2004-02-26, Victoriasalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-22Bibliographically approved

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