Universität zu Köln

Tonnus, Wulf, Meyer, Claudia, Paliege, Alexander, Belavgeni, Alexia ORCID: 0000-0001-6311-5858, von Maessenhausen, Anne, Bornstein, Stefan R., Hugo, Christian, Becker, Jan Ulrich ORCID: 0000-0003-2929-8085 and Linkermann, Andreas ORCID: 0000-0001-6287-9725 (2019). The pathological features of regulated necrosis. J. Pathol., 247 (5). S. 697 - 708. HOBOKEN: WILEY. ISSN 1096-9896

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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 (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tonnus, Wulf UNSPECIFIED UNSPECIFIED UNSPECIFIED Meyer, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Paliege, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Belavgeni, Alexia UNSPECIFIED orcid.org/0000-0001-6311-5858 UNSPECIFIED von Maessenhausen, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Bornstein, Stefan R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hugo, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Jan Ulrich UNSPECIFIED orcid.org/0000-0003-2929-8085 UNSPECIFIED Linkermann, Andreas UNSPECIFIED orcid.org/0000-0001-6287-9725 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-153142
DOI:	10.1002/path.5248
Journal or Publication Title:	J. Pathol.
Volume:	247
Number:	5
Page Range:	S. 697 - 708
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1096-9896
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NECROPTOTIC CELL-DEATH; NF-KAPPA-B; RIP KINASES; GASDERMIN-D; IN-VIVO; MEDIATES NECROPTOSIS; NLRP3 INFLAMMASOME; MOLECULAR SWITCH; ACTIVATION; MLKL Multiple languages Oncology; Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15314