Pharmacologic modulation of systemic inorganic phosphate levels restores the impaired phagocytosis of Kupffer cells and improves liver function in murine models of chronic liver failure.

Chronic liver disease induced by various etiologies (ethanol, viruses, etc.) impairs macrophage phagocytosis. This study demonstrated that such impairment could be alleviated by systemic weak phosphate stress in vitro and in vivo. A cell model of ethanol-induced damage was established by incubating the RAW 264.7 cell line in a low-phosphate medium, and the phagocytic capacity of the injured cells was increased, as evidenced by their increased ability to engulf Escherichia coli and fluorescent microspheres. The transcriptomic analysis combined with laboratory validation by qPCR and Western blotting identified the PI3K-Akt signaling pathway and RAC3 protein as potential contributors. The expression of FcγR was inhibited after injury, but low Pi stress increased its expression to normal levels for foreign body recognition. Moreover, actin polymerization was also increased, which is beneficial for phagosome formation. In both alcohol- and DEN-induced models of chronic liver injury, alcohol exposure led to a decreased phagocytic capacity of liver macrophages (Kupffer cells), which was mitigated by the oral administration of sevelamer (5 % w/w). Immunohistochemical results confirmed the findings from the cellular experiments, revealing consistent expression patterns of FcγR, RAC3, and PI3K-Akt. Furthermore, damage to liver function was ameliorated in both models. In conclusion, these results indicate that the weak phosphate stress induced by sevelamer has therapeutic potential to reverse the impairment of phagocytosis caused by liver injury.