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VWF-mediated thromboinflammation in stroke
potentially via its A1 domain, was able to directly interact with PSGL-1 and several β2 integrins on leukocytes.47 PSGL-1 and β2 integrins are present on monocytes, neu- trophils and T cells and their interaction with VWF is one possible mechanism by which VWF could recruit leuko- cytes in the ischemic brain. Another mechanism by which VWF most likely recruits leukocytes involves platelets that are bound to the VWF A1 domain via their GPIba recep- tor. Platelets can subsequently bind leukocytes through well-established interactions.48 This VWF-platelet mediat- ed leukocyte recruitment was previously presented in an elegant study by Petri and colleagues.49 They observed that peritoneal inflammation triggered the release and cell surface deposition of endothelial VWF which allowed platelets to adhere to the endothelium via GPIba and sub- sequently recruit leukocytes. Blocking VWF or depleting platelets had an equally strong anti-inflammatory effect in their model, highlighting the inflammatory role of VWF- associated platelets. A similar course of events is most likely also occurring in the ischemic brain. The detrimen- tal interaction between VWF and platelets has already been extensively studied in the setting of stroke.15,17,19 Our results again highlight the importance of the inflammatory component of the VWF-GPIba interaction in the ischemic stroke brain. Furthermore, our findings corroborate the observations of Schuhmann et al., who, after inhibition of platelet GPIba, also observed an attenuated inflammatory response, which protected mice from cerebral ischemia- reperfusion injury.50
Our study has some limitations that need to be addressed. First, all outcomes were measured at 24 h after ischemic stroke. This time-point was chosen to specifical- ly investigate the early, acute inflammatory response after stroke. Nevertheless, it was previously shown that leuko- cyte infiltration peaks at 72 h after ischemic stroke in mice.51 It would be interesting to investigate VWF-medi- ated inflammatory responses at later time-points or even during initial ischemia. Second, the set-up of our study did not allow identification of the specific interactions that mediate leukocyte-platelet or leukocyte-VWF bind-
ing in the setting of ischemic stroke. Specific inhibitors of platelet-leukocyte or VWF-leukocyte interactions would be needed to further elucidate the specific leukocyte interactions. Lastly, histology or flow cytometric analysis of brain tissue will not perfectly reflect the dynamic inflammatory processes going on in the ischemic stroke brain. Future studies are needed to visualize VWF- platelet-leukocyte interactions in vivo by, for example, intravital microscopy.
In conclusion, we found that VWF is involved in the recruitment of inflammatory monocytes, neutrophils and T cells to the ischemic brain via its A1 domain. Inhibition of VWF-mediated thromboinflammation, for example by blocking the VWF A1-GPIba interaction, or by cleaving VWF with ADAMTS13,4 could become a promising treat- ment strategy for the prevention of cerebral ischemia/reperfusion injury.
Disclosures
No conflicts of interest to disclose
Contributions
FD designed the study, acquired, analyzed and interpreted the data and wrote the manuscript. SFDM conceived and designed the study, analyzed and interpreted the data and wrote the manuscript. KM acquired and analyzed data and reviewed the manuscript. AV performed experiments. CVD and PJL pro- vided essential reagents and reviewed the manuscript. HD and KV reviewed the manuscript.
Funding
This work was supported by Fonds voor Wetenschappelijk Onderzoek - Vlaanderen (research grants G.0A86.13, G.0785.17 and 1509216N to SFDM), by research grants from KU Leuven (OT/14/099 and ISP/14/02L2 to SFDM) and by a research grant from the Queen Elisabeth Medical Foundation (to SFDM). FD is a postdoctoral fellow of Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO, 12U7818N). KM was a H2020 Marie Skłodowska-Curie Actions fellow (under agreement number 747993, “VWF and NETs”).
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