Sublethal necroptosis signaling promotes inflammation and liver cancer
- Author(s)
- Vucur, M; Ghallab, A; Schneider, AT; Adili, A; Cheng, M; Castoldi, M; Singer, MT; Büttner, V; Keysberg, LS; Küsgens, L; Kohlhepp, M; Görg, B; Gallage, S; Barragan Avila, JE; Unger, K; Kordes, C; Leblond, AL; Albrecht, W; Loosen, SH; Lohr, C; Jördens, MS; Babler, A; Hayat, S; Schumacher, D; Koenen, MT; Govaere, O; Boekschoten, MV; Jörs, 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;
- Details
- Publication Year 2023-06-12,Volume 56,Issue #7,Page 1578-1595 e8
- Journal Title
- Immunity
- Abstract
- 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.
- Publisher
- Cell Press
- Keywords
- Hcc; Mlkl; Nf-κb; Rip1; Rip3; Ripk1; Ripk3; Traf2; intravital imaging; undead cells
- Research Division(s)
- Inflammation
- PubMed ID
- 37329888
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2023.05.017
- Open Access at Publisher's Site
https://doi.org/10.1016/j.immuni.2023.05.017- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-06-30 02:16:29
Last Modified: 2023-07-21 09:57:46