Platelet-mediated inhibition of polymorphonuclear neutrophil apoptosis

Abstract: 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.