Molecular Markers of Regulated Necrosis Enable Pathological Detection of Targetable Cell Death Pathways
This review describes how necroptosis, pyroptosis, and ferroptosis can now be detected in tissue using specific antibodies against phosphorylated MLKL, cleaved gasdermins, and oxidative lipid signatures via oxylipidomics mass spectrometry. With clinical trials underway for inhibitors of each pathway (necrostatins, ferrostatins, inflammasome blockers), pathological identification of specific necrosis mechanisms could guide therapy selection. The authors urge pathologists to adopt these ancillary tests alongside established apoptosis markers.
The original study
The pathological features of regulated necrosis.
- Authors
- Tonnus W, Meyer C, Paliege A, Belavgeni A, von Mässenhausen A, Bornstein SR, et al.
- Journal
- The Journal of pathology
- Type
- Journal Article, Research Support, Non-U.S. Gov't, Review
- PMID
- 30714148
Original abstract
Necrosis of a cell is defined by the loss of its plasma membrane integrity. Morphologically, necrosis occurs in several forms such as coagulative necrosis, colliquative necrosis, caseating necrosis, fibrinoid necrosis, and others. Biochemically, necrosis was demonstrated to represent a number of genetically determined signalling pathways. These include (i) kinase-mediated necroptosis, which depends on receptor interacting protein kinase 3 (RIPK3)-mediated phosphorylation of the pseudokinase mixed lineage kinase domain like (MLKL); (ii) gasdermin-mediated necrosis downstream of inflammasomes, also referred to as pyroptosis; and (iii) an iron-catalysed mechanism of highly specific lipid peroxidation named ferroptosis. Given the molecular understanding of the nature of these pathways, specific antibodies may allow direct detection of regulated necrosis and correlation with morphological features. Necroptosis can be specifically detected by immunohistochemistry and immunofluorescence employing antibodies to phosphorylated MLKL. Likewise, it is possible to generate cleavage-specific antibodies against epitopes in gasdermin protein family members. In ferroptosis, however, specific detection requires quantification of oxidative lipids by mass spectrometry (oxylipidomics). Together with classical cell death markers, such as TUNEL staining and detection of cleaved caspase-3 in apoptotic cells, the extension of the arsenal of necrosis markers will allow pathological detection of specific molecular pathways rather than isolated morphological descriptions. These novel pieces of information will be extraordinarily helpful for clinicians as inhibitors of necroptosis (necrostatins), ferroptosis (ferrostatins), and inflammasomes have emerged in clinical trials. Anatomical pathologists should embrace these novel ancillary tests and the concepts behind them and test their impact on diagnostic precision, prognostication, and the prediction of response to the upcoming anti-necrotic therapies. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.