Functional Ly6G knock-out increases mortality in a gender-dependent manner following reperfused acute myocardial infarction
B Zschieschack, S Korste, E Haj Yehia, P Stock, N Hagemann, M Gunzer, U B Hendgen Cotta, T Rassaf, M TotzeckAbstract
Background
Myocardial infarction (MI) is still the leading cause of death worldwide. Following MI, immune cells infiltrate the former ischemic tissue with neutrophils being the first and most prominent cells in the acute phase. Cell-cell interaction and cytokine/chemokine sensing determine the overall function of these cells. The common neutrophil marker Ly6G, for which no function is known so far, has been discussed to interact with several proteins involved in these processes. We hypothesized that Ly6G therefor can influence outcome following MI.
Methods & Results
For our experiments, we used the catchup mouse model, which contains a tdTomato and LoxCre insertion at the Ly6G locus. We isolated neutrophils from the bone marrow of both male and female mice and compared homozygous and heterozygous catchup neutrophils with wild type C57BL/6 neutrophils. Catchup neutrophils phagocytosed apoptotic cardiomyocytes about 5 times more than wild type cells did. In an in vitro assay, catchup neutrophils stimulated with PMA showed decreased motility. Using the Seahorse analyzer to investigate cellular respiration and oxidative burst potential, we could not find a difference between the genotypes. In an in vivo model, male homozygous catchup mice showed increased mortality in the first 3 days following reperfused acute myocardial infarction (repAMI), which was not observable in female mice. Similarly, heart function, tissue damage and scar size were comparable in female mice, while surviving male homozygous mice showed increased acute tissue damage and scar size compared to heterozygous animals.
Conclusion
We could show that Ly6G seems to play a role in neutrophil phagocytosis, as well as cellular motility. Furthermore, there seems to be a gender-dependent manner, which influences survival and tissue damage. Further studies are needed to investigate the mechanism underlying this gender dimorphism and the overall pathway by which neutrophils void of Ly6G worsen outcome.