Paving the way for precision medicine v2.0 in intensive care by profiling necroinflammation in biofluids

Schematic simplification of different modes of parenchymal and immune cell death. Organismal homeostasis is based on a balance between cell renewal and death, which is mediated by apoptosis. Apoptotic blebbing allows quick phagocytic uptake and recycling, which prevents leakage of the cellular content and subsequent inflammation (Arrow 1). In the absence or lack of sufficient phagocytic capacity (Arrow 2), apoptotic caspases cleave Gasdermin E (GSDME) resulting in cell rupture, referred to as secondary necrosis. Similarly, inflammatory caspases cleave Gasdermin D (GSDMD) to induce pyroptosis. Necroptosis is executed by the concerted action of RIPK3 kinase activity and the pseudokinase MLKL, whereas ferroptosis is fulfilled by free radical-induced lipid peroxidation catalyzed by Fe(II). Neutrophils typically die by netosis along expelling neutrophil extracellular traps (NETs), which is dependent on autophagy processes and PAD4-mediated citrullination. Different molecular mechanisms execute plasma membrane rupture, resulting in cellular leakage, defined as necrosis. Release of damage-associated molecular patterns (DAMPs) and inflammatory signaling by necrotic cells subsequently induce inflammatio