It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncov-ered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant ne-crosome and NF -KB activation in hepatocytes, which physiologically express low concentrations of recep-tor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sub-lethal"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 -KB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intra-tumoral NF-KB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogene-sis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a carcinoma.
Sublethal necroptosis signaling promotes inflammation and liver cancer / M. Vucur, A. Ghallab, A.T. Schneider, A. Adili, M. Cheng, M. Castoldi, M.T. Singer, V. Büttner, L.S. Keysberg, L. Küsgens, M. Kohlhepp, B. Görg, S. Gallage, J.E. Barragan Avila, K. Unger, C. Kordes, A. Leblond, W. Albrecht, S.H. Loosen, C. Lohr, M.S. Jördens, A. Babler, S. Hayat, D. Schumacher, M.T. Koenen, O. Govaere, M.V. Boekschoten, S. Jörs, C. Villacorta-Martin, V. Mazzaferro, J.M. Llovet, R. Weiskirchen, J.N. Kather, P. Starlinger, M. Trauner, M. Luedde, L.R. Heij, U.P. Neumann, V. Keitel, J.G. Bode, R.K. Schneider, F. Tacke, B. Levkau, T. Lammers, G. Fluegen, T. Alexandrov, A.L. Collins, G. Nelson, F. Oakley, D.A. Mann, C. Roderburg, T. Longerich, A. Weber, A. Villanueva, A.L. Samson, J.M. Murphy, R. Kramann, F. Geisler, I.G. Costa, J.G. Hengstler, M. Heikenwalder, T. Luedde. - In: IMMUNITY. - ISSN 1074-7613. - 56:7(2023), pp. 1578-1595. [10.1016/j.immuni.2023.05.017]
Sublethal necroptosis signaling promotes inflammation and liver cancer
V. Mazzaferro;
2023
Abstract
It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncov-ered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant ne-crosome and NF -KB activation in hepatocytes, which physiologically express low concentrations of recep-tor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sub-lethal"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 -KB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intra-tumoral NF-KB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogene-sis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a carcinoma.
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