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Sublethal necroptosis signaling promotes inflammation and liver cancer

Lookup NU author(s): Amy Collins, Dr Glyn NelsonORCiD, Professor Fiona OakleyORCiD, Professor Derek Mann

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
031L0257D
1172929
1461704932
2002965
279874820
57584079
272983813
314905040
441891347-P10
457840828
667273
771083
9000719
BMG—DEEP LIVER 2520DAT111
CANTAR—NW21-062E
C18342/A23390Cancer Research UK CRUK (open competition)
Deutsche Krebshilfe 70114893
Deutsche Krebshilfe —70114893
DFG – SCHN 1659/1-1
C9380/A18084Cancer Research UK CRUK (open competition)
CA830/3-1
C-TIP-HCC 031L0257G
FKZ 031L0045
FKZ 031L0052
SFB-TR209
SFB-CRC 1382 Project A01
SNF 320030-182764

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