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  • Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis.

Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis.

The Journal of experimental medicine (2019-01-17)
Ludwig T Weckbach, Ulrich Grabmaier, Andreas Uhl, Sebastian Gess, Felicitas Boehm, Annette Zehrer, Robert Pick, Melanie Salvermoser, Thomas Czermak, Joachim Pircher, Noah Sorrelle, Mary Migliorini, Dudley K Strickland, Karin Klingel, Volker Brinkmann, Ulrike Abu Abed, Urs Eriksson, Steffen Massberg, Stefan Brunner, Barbara Walzog
ABSTRACT

Heart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Low-density lipoprotein receptor-related protein 1 (LRP1) acts as the functionally relevant receptor for MK-induced PMN recruitment as well as NET formation. In summary, NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation.