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Vucur, M.* ; Ghallab, A.* ; Schneider, A.T.* ; Adili, A.* ; Cheng, M.* ; Castoldi, M.* ; Singer, M.T.* ; Büttner, V.* ; Keysberg, L.S.* ; Küsgens, L.* ; Kohlhepp, M.* ; Görg, B.* ; Gallage, S.* ; Barragan Avila, J.E.* ; Unger, K. ; Kordes, C.* ; Leblond, A.L.* ; Albrecht, W.* ; Loosen, S.H.* ; Lohr, C.* ; Jördens, M.S.* ; Babler, A.* ; Hayat, S.* ; Schumacher, D.* ; Koenen, M.T.* ; Govaere, O.* ; Boekschoten, M.V.* ; Jors, S.* ; Villacorta-Martin, C.* ; Mazzaferro, V.* ; Llovet, J.M.* ; Weiskirchen, R.* ; Kather, J.N.* ; Starlinger, P.* ; Trauner, M.* ; Luedde, M.* ; Heij, L.R.* ; Neumann, U.P.* ; Keitel, V.* ; Bode, J.G.* ; Schneider, R.K.* ; Tacke, F.* ; Levkau, B.* ; Lammers, T.* ; Fluegen, G.* ; Alexandrov, T.* ; Collins, A.L.* ; Nelson, G.* ; Oakley, F.* ; Mann, D.A.* ; Roderburg, C.* ; Longerich, T.* ; Weber, A.* ; Villanueva, A.* ; Samson, A.L.* ; Murphy, J.M.* ; Kramann, R.* ; Geisler, F.* ; Costa, I.G.* ; Hengstler, J.G.* ; Heikenwälder, M.* ; Luedde, T.*

Sublethal necroptosis signaling promotes inflammation and liver cancer.

Immunity 56, 1578-1595.e8 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Hcc ; Intravital Imaging ; Mlkl ; Nf-κb ; Rip1 ; Rip3 ; Ripk1 ; Ripk3 ; Traf2 ; Undead Cells; Nf-kappa-b; Gene-expression Signature; Cell-death; Hepatocellular-carcinoma; Mouse Hepatocytes; Activation; Traf2; Rip3; Tak1; Hepatocarcinogenesis
ISSN (print) / ISBN 1074-7613
e-ISSN 1097-4180
Journal Immunity
Quellenangaben Volume: 56, Issue: 7, Pages: 1578-1595.e8 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Radiation Cytogenetics (ZYTO)
Grants Cancer Research UK