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Lookup NU author(s): Amy Collins, Dr Glyn NelsonORCiD, Professor Fiona OakleyORCiD, Professor Derek Mann
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 The Author(s)It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged “sublethal” state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.
Author(s): Vucur M, Ghallab A, Schneider AT, Adili A, Cheng M, Castoldi M, Singer MT, Buttner V, Keysberg LS, Kusgens L, Kohlhepp M, Gorg B, Gallage S, Barragan Avila JE, Unger K, Kordes C, Leblond A-L, Albrecht W, Loosen SH, Lohr C, Jordens MS, Babler A, Hayat S, Schumacher D, Koenen MT, Govaere O, Boekschoten MV, Jors S, Villacorta-Martin C, Mazzaferro V, Llovet JM, Weiskirchen R, Kather JN, Starlinger P, Trauner M, Luedde M, Heij LR, Neumann UP, Keitel V, Bode JG, Schneider RK, Tacke F, Levkau B, Lammers T, Fluegen G, Alexandrov T, Collins AL, Nelson G, Oakley F, Mann DA, Roderburg C, Longerich T, Weber A, Villanueva A, Samson AL, Murphy JM, Kramann R, Geisler F, Costa IG, Hengstler JG, Heikenwalder M, Luedde T
Publication type: Article
Publication status: Published
Journal: Immunity
Year: 2023
Volume: 56
Issue: 7
Pages: 1578-1595.e8
Print publication date: 11/07/2023
Online publication date: 16/06/2023
Acceptance date: 22/05/2023
Date deposited: 02/08/2023
ISSN (print): 1074-7613
ISSN (electronic): 1097-4180
Publisher: Cell Press
URL: https://doi.org/10.1016/j.immuni.2023.05.017
DOI: 10.1016/j.immuni.2023.05.017
PubMed id: 37329888
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