- Platelets regulate neutrophil histotoxic activities and prevent bleeding during immune complex-mediated inflammation by a glycoprotein VI-dependent repairing action
GROS A1, LAMRANI L1, OLLIVIER V1, SYVANNARATH V1, NIESWANDT B2, JANDROT-PERRUS M1, HO-TIN-NOE B1.
1UMRS-1148 Inserm-University Paris Diderot Laboratory for Vascular Translational Science, Bichat Hospital, Paris, France;
2Chair of Vascular Medicine, University Hospital Würzburg & Rudolf Virchow Center, University of Würzburg, Germany.
Introduction- Platelets are now recognized as important actors of immune responses, in part because of their ability to enhance leukocyte infiltration. In addition, it has been demonstrated in mice that platelets are critical to maintain the vascular integrity in various inflamed tissues. Although a recent study suggests that platelet ITAMs are involved in this mechanism, it remains unclear what platelets do to prevent inflammatory bleeding. However, there is experimental evidence suggesting that this protective effect could involve dampening of neutrophil damaging activities by platelets. Therefore, one aim of our project is to determine whether platelets dampen neutrophil histotoxic activities and/or repair neutrophil-inflicted vascular damages.
Methods- Using in vitro experiments on purified human neutrophils and platelets, and models of immune complex-mediated dermatitis and peritonitis combined with immunodepletion of platelets and/or neutrophils in wild-type and/or glycoprotein VI (GPVI) deficient mice, we investigated the contribution of platelets to the regulation of neutrophil infiltration and histotoxic activities. We further analyzed the involvement of GPVI in the recruitment of platelets to inflamed microvessels using intravital microscopy.
Results- Depletion of neutrophils prevented skin bleeding observed in thrombocytopenic and GPVI-deficient mice subjected to dermatitis, indicating that platelets counter the deleterious effect of neutrophils. Co-incubation of isolated human neutrophils and platelets revealed that levels of neutrophil-derived myeloperoxidase, elastase, and reactive oxygen species were significantly decreased by platelets. However, during dermatitis and peritonitis, similarly to neutrophil infiltration, levels of neutrophil MMP-9 and myeloperoxidase were comparable or even reduced in GPVI-deficient and thrombocytopenic mice as compared to wild-type mice. We further show that during dermatitis, intravascular binding sites for GPVI are exposed specifically where neutrophil accumulate, and that GPVI supports the recruitment of platelets to these spots.
Conclusion- We show that although platelets can limit neutrophil histotoxic activities, bleeding prevention by platelets during immune complex-mediated dermatitis most likely rely on a GPVI-dependent repairing action.