Sublethal necroptosis signaling promotes inflammation and liver cancer
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
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.
Details
Originalsprache | Englisch |
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Seiten (von - bis) | 1578-1595.e8 |
Fachzeitschrift | Immunity |
Jahrgang | 56 |
Ausgabenummer | 7 |
Publikationsstatus | Veröffentlicht - 11 Juli 2023 |
Peer-Review-Status | Ja |
Externe IDs
PubMed | 37329888 |
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Schlagworte
Ziele für nachhaltige Entwicklung
ASJC Scopus Sachgebiete
Schlagwörter
- HCC, intravital imaging, MLKL, NF-κB, RIP1, RIP3, RIPK1, RIPK3, TRAF2, undead cells