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Publication : Sublethal necroptosis signaling promotes inflammation and liver cancer.

First Author  Vucur M Year  2023
Journal  Immunity Volume  56
Issue  7 Pages  1578-1595.e8
PubMed ID  37329888 Mgi Jnum  J:338216
Mgi Id  MGI:7511353 Doi  10.1016/j.immuni.2023.05.017
Citation  Vucur M, et al. (2023) Sublethal necroptosis signaling promotes inflammation and liver cancer. Immunity 56(7):1578-1595.e8
abstractText  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-kappaB 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-kappaB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-kappaB-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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