Accéder au contenu
Merck

RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis.

Cancer immunology research (2020-03-04)
Lei Wu, Xiao Zhang, Lu Zheng, Huakan Zhao, Guifang Yan, Qi Zhang, Yu Zhou, Juan Lei, Jiangang Zhang, Jingchun Wang, Rong Xin, Lu Jiang, Jin Peng, Qian Chen, Sin Man Lam, Guanghou Shui, Hongming Miao, Yongsheng Li
RÉSUMÉ

Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)-associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
Collagénase from Clostridium histolyticum, suitable for release of physiologically active rat hepatocytes, Type IV, 0.5-5.0 FALGPA units/mg solid, ≥125 CDU/mg solid
Référence
Conditionnement
Disponibilité
Prix
Quantité
Sigma-Aldrich
Roténone, ≥95%
Référence
Conditionnement
Disponibilité
Prix
Quantité
Sigma-Aldrich
Cyanure de 4-(trifluorométhoxy)phénylhydrazone carbonyle, ≥98% (TLC), powder
Référence
Conditionnement
Disponibilité
Prix
Quantité
Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O55:B5, purified by ion-exchange chromatography, TLR ligand tested
Référence
Conditionnement
Disponibilité
Prix
Quantité
Sigma-Aldrich
N-Nitrosodiethylamine, liquid
Référence
Conditionnement
Disponibilité
Prix
Quantité
Sigma-Aldrich
RIPK3 Inhibitor, GSK′872
Référence
Conditionnement
Disponibilité
Prix
Quantité
Sigma-Aldrich
TOFA, ≥98% (HPLC)
Référence
Conditionnement
Disponibilité
Prix
Quantité
Sigma-Aldrich
Amyloid Protein Non-Aβ Component, ≥80% (HPLC)
Référence
Conditionnement
Disponibilité
Prix
Quantité
Supelco
Citrinin solution, ~100 μg/mL in acetonitrile, analytical standard
Référence
Conditionnement
Disponibilité
Prix
Quantité