Sublethal necroptosis signaling promotes inflammation and liver cancer.

Vucur, Mihael; Ghallab, Ahmed; Schneider, Anne T; Adili, Arlind; Cheng, Mingbo; Castoldi, Mirco; Singer, Michael T; Büttner, Veronika; Keysberg, Leonie S; Küsgens, Lena; Kohlhepp, Marlene; Görg, Boris; Gallage, Suchira; Barragan Avila, Jose Efren; Unger, Kristian; Kordes, Claus; Leblond, Anne-Laure; Albrecht, Wiebke; Loosen, Sven H; Lohr, Carolin; Jördens, Markus S; Babler, Anne; Hayat, Sikander; Schumacher, David; Koenen, Maria T; Govaere, Olivier; Boekschoten, Mark V; Jörs, Simone; Villacorta-Martin, Carlos; Mazzaferro, Vincenzo; Llovet, Josep M; Weiskirchen, Ralf; Kather, Jakob N; Starlinger, Patrick; Trauner, Michael; Luedde, Mark; Heij, Lara R; Neumann, Ulf P; Keitel, Verena; Bode, Johannes G; Schneider, Rebekka K; Tacke, Frank; Levkau, Bodo; Lammers, Twan; Fluegen, Georg; Alexandrov, Theodore; Collins, Amy L; Nelson, Glyn; Oakley, Fiona; Mann, Derek A; Roderburg, Christoph; Longerich, Thomas; Weber, Achim; Villanueva, Augusto; Samson, Andre L; Murphy, James M; Kramann, Rafael; Geisler, Fabian; Costa, Ivan G; Hengstler, Jan G; Heikenwalder, Mathias; Luedde, Tom     «

Vucur, Mihael; Ghallab, Ahmed; Schneider, Anne T; Adili, Arlind; Cheng, Mingbo; Castoldi, Mirco; Singer, Michael T; Büttner, Veronika; Keysberg, Leonie S; Küsgens, Lena; Kohlhepp, Marlene; Görg, Boris; Gallage, Suchira; Barragan Avila, Jose Efren; Unger, Kristian; Kordes, Claus; Leblond, Anne-Laure; Albrecht, Wiebke; Loosen, Sven H; Lohr, Carolin; Jördens, Markus S; Babler, Anne; Hayat, Sikander; Schumacher, David; Koenen, Maria T; Govaere, Olivier; Boekschoten, Mark V; Jörs, Simone; Villacorta-...     »

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.      «

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 int...     »