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. 2019 Aug 21;10:1920. doi: 10.3389/fimmu.2019.01920

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Copyright © 2019 Lackner, Weber, Baur, Haffner-Luntzer, Eiseler, Fois, Gebhard, Relja, Marzi, Pfeifer, Halvachizadeh, Lipiski, Cesarovic, Pape, Kalbitz and TREAT Research Group.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic representation of systemic inflammation after trauma and during sepsis. After trauma Midkine is released systemically. Midkine recruits polymorphonuclear neutrophils (PMNs) and induces the release of extracellular traps (NETosis) via the receptor-related protein 1 (LRP1) on the neutrophils, which was demonstrated by Weckbach et al. (23), (1). The neutrophil extracellular traps (NETs) include extracellular histones, which act via toll-like receptors (TLRs) on the surface of cardiomyocytes, inducing cardiac dysfunction and cardiac damage. Furthermore, Midkine is able to act detrimental on human cardiomyocytes by direct interactions via TLR4, TLR9, and pyrogenic receptor subtype 7 (P2X7), inducing enhanced apoptosis, disturbing calcium signaling and impairing mitochondrial respiration (2, Hypothesis of this manuscript). Additionally, after trauma and during sepsis the complement factors C5a and C3a are released systemically. Both act directly via their receptors (C5aR, C3aR) on cardiomyocytes, leading to cardiac dysfunction. Moreover, the complement factors also induce NETosis of neutrophils via their receptors.