Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb

David Köhler,Helene A Häberle,Tamam Bakchoul,Tiago Granja,Peter Rosenberger,Ekaterina Legchenko,Tobias Geisler,Harald F Langer,Bernhard Nieswandt,Michael Koeppen,Julia Volz,Claudia Eggstein,Georg Hansmann

doi:10.1038/s41467-020-14958-x

Abstract

Myocardial ischemia is one of the leading health problems worldwide. Therapy consists of the restitution of coronary perfusion which is followed by myocardial inflammation. Platelet–neutrophil interaction is a crucial process during inflammation, yet its consequences are not fully understood. Here, we show that platelet–neutrophil complexes (PNCs) are increased in patients with acute myocardial infarction and that this is associated with increased levels of neuronal guidance protein semaphorin 7A (SEMA7A). To investigate this further, we injected WT animals with Sema7a and found increased infarct size with increased numbers of PNCs. Experiments in genetically modified animals identify Sema7a on red blood cells to be crucial for this condition. Further studies revealed that Sema7a interacts with the platelet receptor glycoprotein Ib (GPIb). Treatment with anti-Sema7a antibody protected from myocardial tissue injury. In summary, we show that Sema7a binds to platelet GPIb and enhances platelet thrombo-inflammatory activity, aggravating post-ischemic myocardial tissue injury.

Highlights

Myocardial ischemia is one of the leading health problems worldwide
We report here that soluble semaphorin 7A (SEMA7A) is elevated in plasma of patients with acute M yocardial infarction (MI), and that Semaphorin 7A holds significant impact on the extent of MIRI
In an attempt to better understand the interaction of platelets and neutrophils and the formation of platelet–neutrophil complexes (PNCs) during inflammatory myocardial injury, we obtained blood samples from patients with active myocardial ischemia and tested them for the presence of PNCs by FACS analysis

Summary

Introduction

Myocardial ischemia is one of the leading health problems worldwide. Therapy consists of the restitution of coronary perfusion which is followed by myocardial inflammation. Histological sections revealed increased tissue injury in Sema7a-injected animals compared to Fc controls and a reduced number of PNCs in the tissue areas at risk (Fig. 2c, d). E Representative flow-cytometric plots of PNCs in the blood of sham animals, rmSema7a- or IgG Fc control–treated mice, showing GPIb (CD42b) and P-selectin (CD62P) after 1 and 120 min reperfusion.

Results

Conclusion