Yin-chen Wu-ling powder inhibits MAPKs/CXCL1/CXCR2-induced neutrophil infiltration to alleviate LPS/D-GalN-induced acute liver failure

Ethnopharmacological relevance: Acute liver failure (ALF) is the result of progression from acute liver injury with high mortality, and novel treatments are needed. Yin-chen Wu-ling powder (YWP), a traditional herbal medicine in China, has been used for treating acute liver injury for thousands of years. However, the mechanism of YWP is unknown.

Aim of the study: In vitro and in vivo studies were conducted to clarify YWP's protective effect on ALF and investigate its hepatoprotective mechanism.

Materials and methods: We established an LPS/D-GalN-induced ALF mouse model and in vitro system to evaluate the effect of YWP. We characterized YWP's chemical composition via UHPLC-Q-Exactive Orbitrap HRMS. Enzyme-linked immunosorbent assay, hematoxylin and eosin staining, immunohistochemistry and immunofluorescence, flow cytometry, qPCR, Western blot were used to discover key mechanisms both in vitro and in vivo.

Results: YWP alleviated liver dysfunction and liver necrosis. YWP reduced hepatocyte death and inflammatory responses. Importantly, YWP markedly inhibited neutrophil infiltration into the liver. We examined key chemokines that contribute to neutrophil recruitment. The results showed that YWP inhibited CXCL1, which is sourced from inflammation-activated hepatocytes. In addition, YWP inhibited TNF-α-induced CXCL1 transcription via the inhibition of MAPKs signaling in vitro. Furthermore, the anti-ALF effect of YWP was weakened when CXCL1/CXCR2 signaling was suppressed.

Conclusion: YWP alleviates inflammatory liver injury in ALF by suppressing neutrophil infiltration into the liver, potentially through inhibition of the MAPKs/CXCL1/CXCR2 axis. We suggest that YWP is a potential anti-inflammatory treatment for ALF.

Acute liver failure; CXCL1; MAPKs; Neutrophil; Pharmaceutical ingredients; Yin-chen Wu-ling powder.