S284: HEPATOCYTE TOLL-LIKE RECEPTORS MEDIATE THE HEPCIDIN INFLAMMATORY RESPONSE TO PATHOGENS AND PATHOGEN-DERIVED LIGANDS

作者：Katharina Bonitz, Silvia Colucci, Richard Sparla, Ruiyue Qiu, Sandro Altamura, Katja Muedder, Stefan Zimmermann, Martina U. Muckenthaler, Oriana Marques · 发表于：HemaSphere · 年份：2023 · DOI：10.1097/01.hs9.0000968048.66647.c5 · 被引用次数：2 · 研究领域：Hepatitis B Virus Studies、Iron Metabolism and Disorders

Background: Iron restriction is an innate immune mechanism that limits the replication of extracellular pathogens. During an infection, innate immune cells detect pathogen-associated molecular patterns (PAMPs) via Toll-like receptors (TLRs) and produce proinflammatory cytokines that contribute to systemic inflammation. Macrophage-derived Interleukin (IL)-6 is detected by hepatocytes, promoting the acute-phase response and the production of the master regulator of systemic iron flows – hepcidin. Hepcidin blocks iron export via ferroportin from duodenal enterocytes and macrophages, a process that leads to iron retention, reduced plasma iron availability and anemia of inflammation (AI). Due to the production of proteins participating in pathogen removal – such as hepcidin – hepatocytes are increasingly recognized as a critical cell type of the innate immune system. Aims: We asked the question whether TLRs expressed on hepatocytes recognize PAMPs, activate hepcidin expression and contribute to iron restriction. Methods: Primary murine hepatocytes were stimulated with ligands targeting TLRs 1-9 and mRNA expression and cytokine secretion was analyzed. Signaling pathways were inhibited by treatment with pharmacological inhibitors or RNA interference of upstream mediators and confirmed by protein analysis of phosphorylation targets. A hepatocyte:macrophage co-culture system was established with primary murine hepatocytes and bone-marrow derived macrophages. Co-culturing conditions in...