National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China; The Liver and Spleen Diseases Research Center, Xi'an, China.
National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China; The Liver and Spleen Diseases Research Center, Xi'an, China; Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Int Immunopharmacol. 2020 Sep;86:106762. doi: 10.1016/j.intimp.2020.106762. Epub 2020 Jul 8.
Splenectomy has been reported to attenuate liver fibrosis. In addition, phenotype transitions of infiltrating macrophages, including Ly6C and Ly6C, 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.
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 Ly6C and Ly6C 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.
Splenectomy alleviated the liver inflammation and fibrosis and also promoted the phenotypic switch of infiltrating macrophages to a Ly6C phenotype in fibrotic liver. The p-ERK1/2 expression was upregulated in macrophages at the same time. Furthermore, splenectomy increased the percentage of Ly6C macrophages and decreased the percentage of Ly6C macrophages both in vivo and in vitro, which was reversed by SCH772984.
Splenectomy attenuates both the liver fibrosis and inflammation, and promotes the phenotype switch of infiltrating macrophages to an anti-inflammatory Ly6C phenotype by activating the ERK1/2 pathway during liver fibrosis.
脾切除术已被报道可减轻肝纤维化。此外，浸润巨噬细胞的表型转变，包括 Ly6C 和 Ly6C，在肝纤维化中起着至关重要的作用。然而，脾脏是否可以调节巨噬细胞的表型转换及其潜在机制仍不清楚。
通过腹腔注射四氯化碳在小鼠中诱导慢性肝纤维化。在肝纤维化期间进行脾切除术或假手术，并进行或不进行巨噬细胞耗竭。分析肝纤维化和 Ly6C 和 Ly6C 巨噬细胞的比例。在分离的巨噬细胞中进行 ERK1/2 信号的 Western 印迹，以研究表型转换的潜在机制。用或不用 ERK1/2 抑制剂 SCH772984 预处理的肝总细胞条件培养基刺激 RAW264.7 细胞，并检查 RAW264.7 细胞的表型转换。在体内，对脾切除术小鼠进行 SCH772984 腹腔注射，并检测肝浸润巨噬细胞的表型转换。
脾切除术减轻了肝炎症和纤维化，并促进了纤维化肝脏中浸润巨噬细胞向 Ly6C 表型的表型转换。同时，巨噬细胞中的 p-ERK1/2 表达上调。此外，脾切除术增加了体内和体外 Ly6C 巨噬细胞的百分比，并减少了 Ly6C 巨噬细胞的百分比，这一作用可被 SCH772984 逆转。
脾切除术通过在肝纤维化期间激活 ERK1/2 途径，不仅减轻了肝纤维化和炎症，还促进了浸润巨噬细胞向抗炎性 Ly6C 表型的表型转换。
