The ligation between ERMAP, galectin-9 and dectin-2 promotes Kupffer cell phagocytosis and antitumor immunity.

Kupffer cells, the liver tissue resident macrophages, are critical in the detection and clearance of cancer cells. However, the molecular mechanisms underlying their detection and phagocytosis of cancer cells are still unclear. Using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that the cell-surface transmembrane protein ERMAP expressed on various cancer cells signaled to activate phagocytosis in Kupffer cells and to control of liver metastasis. ERMAP interacted with ß-galactoside binding lectin galectin-9 expressed on the surface of Kupffer cells in a manner dependent on glycosylation. Galectin-9 formed a bridging complex with ERMAP and the transmembrane receptor dectin-2, expressed on Kupffer cells, to induce the detection and phagocytosis of cancer cells by Kupffer cells. Patients with low expression of ERMAP on tumors had more liver metastases. Thus, our study identified the ERMAP-galectin-9-dectin-2 axis as an 'eat me' signal for Kupffer cells.

Salvianolic acid B protects against acute and chronic liver injury by inhibiting Smad2C/L phosphorylation.

Salvianolic acid B (Sal B) has strong antioxidant and anti-fibrosis effects, which are related to the transforming growth factor ß/Smad signaling pathway. However, how Sal B affects this antioxidant pathway and the phosphorylation (p-) of Smad2 at both the COOH-terminal (pSmad2C) and linker region (pSmad2L) are unknown. The aims of the present study were to investigate the underlying mechanisms of Sal B on acute and chronic liver injury induced by CCl4 and H2O2, and its effects on p-Smad2C/L. In in vivo experiments, acute and chronic liver injury models were induced by CCl4, and the oxidative damage cell model was established in vitro with H2O2. Liver histopathology was assessed using hematoxylin and eosin and Van Gieson's staining. Moreover, serum biochemical indicators were analyzed using specific assay kits. Furthermore, the present study evaluated the oxidant/antioxidant status in acute and chronic liver injury models by oxidative stress parameters such as malondialdehyde, glutathione and superoxide dismutase. In addition, western blot analysis was performed to analyze the protein expression levels of pSmad2C, pSmad2L, nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). It was found that Sal B improved liver histology, decreased the levels of aminotransferase and attenuated oxidative stress in acute and chronic liver injury models. Additionally, the protein expression levels of pSmad2C and pSmad2L were decreased, but Nrf2 and HO-1 expression levels were increased both in vivo and in vitro. Collectively, the present results suggested that Sal B may protect against acute and chronic liver injury via inhibition of Smad2C/L phosphorylation, and the Nrf2/HO-1 signaling pathway may play an important role in this process.