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• Splenectomy alleviates the liver inflammation and fibrosis. • Splenectomy promotes the phenotype switch of infiltrating macrophages to Ly6Clow. • Splenectomy activates the ERK1/2 pathway in hepatic macrophages in fibrotic liver. • Inhibitor of ERK1/2 rescues the phenotype switch of macrophages after splenectomy. Background and aim: Splenectomy has been reported to attenuate liver fibrosis. In addition, phenotype transitions of infiltrating macrophages, including Ly6Chigh and Ly6Clow, play an essential role in the liver fibrosis. However, whether the spleen can regulate the phenotype switch of macrophages and the underlying mechanism still remain unclear. Methods: Chronic liver fibrosis in mice was induced by intraperitoneal injection with carbon tetrachloride. Splenectomy or sham operation was performed with or without depletion of macrophages during liver fibrosis. Liver fibrosis and the proportion of Ly6Chigh and Ly6Clow macrophages were analyzed. Western blotting of ERK1/2 signals was performed in isolated macrophages to investigate the underlying mechanism of phenotype transition. RAW264.7 cells were stimulated by liver total cells conditioned medium with or without preincubation of SCH772984, the ERK1/2 inhibitor, and the phenotype switch of RAW264.7 cells was examined. In vivo , intraperitoneal injection of SCH772984 was performed on the splenectomy mice and the phenotype switch of liver infiltrating macrophages was tested. Results: Splenectomy alleviated the liver inflammation and fibrosis and also promoted the phenotypic switch of infiltrating macrophages to a Ly6Clow phenotype in fibrotic liver. The p-ERK1/2 expression was upregulated in macrophages at the same time. Furthermore, splenectomy increased the percentage of Ly6Clow macrophages and decreased the percentage of Ly6Chigh macrophages both in vivo and in vitro , which was reversed by SCH772984. Conclusions: Splenectomy attenuates both the liver fibrosis and inflammation, and promotes the phenotype switch of infiltrating macrophages to an anti-inflammatory Ly6Clow phenotype by activating the ERK1/2 pathway during liver fibrosis. [ABSTRACT FROM AUTHOR]