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Our study aimed to investigate the histologic and immunological changes of portal hypertension (PH) pre- and postsplenectomy in hepatitis B virus (HBV)-related cirrhosis. Peripheral blood samples were obtained from 30 patients with HBV-related cirrhosis and PH at pre- and postsplenectomy time points and from 15 healthy subjects. Spleen tissue specimens were collected from 15 of the patients with HBV-related cirrhosis and from 8 control patients who had undergone splenectomy due to trauma. Immunohistochemical staining was performed to evaluate the immune effector cells and the expression of negative immune regulators. Flow cytometry was used to investigate the immunophenotypes and percentages. The spleen of cirrhotic patients with PH showed extensive depletion of splenic CD4, CD8, and human leukocyte antigen DR cells along with overexpression of the inhibitory receptors programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain-3 and their ligands (PD-L2 and galectin-9). Peripheral blood of patients with PH showed remarkable decrease in proportions of CD8 T cell and natural killer (NK) cells and increase in regulatory T (Treg) cells, as well as high expression of PD-1 in CD4/8 T cells. Compared with presplenectomy patients, cirrhotic patients with PH showed increased proportions of CD8 and NK cells, decreased proportion of Treg cells, and decreased expression of PD-1 in peripheral blood CD4/8 T cells after splenectomy. PH-spleen could lead to peripheral tolerance and immunosuppression in HBV cirrhotic patients, and splenectomy may cause beneficial immunological changes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Immune inflammation and immunosuppression coexist on the spleen during the course of sepsis. • Splenectomy could protect sepsis mice from exhaustion of immune cell by reduction of the expression of Treg cells and PD-1/PD-L1 axis in immune cell during the immunosuppressive stage of sepsis. • Splenectomy also could reduce liver and lung injury possibly by TIM 3 and/or Galectin-9 axis. • The spleen is an important regulator of the occurrence and development of sepsis. The role of the spleen in sepsis is still controversial. Therefore, we investigated the effect of the spleen on sepsis-induced immune dysfunction in C57BL/6 mice subjected to caecal ligation and puncture (CLP). Changes in different immune cells and apoptotic cells in the spleen and peripheral blood were observed 4, 24 and 48 h after CLP. Then, we determined that 48 h following CLP was the most significant period of immunosuppression. Next, we divided the mice into four groups: control, CLP, CLP + spx (splenectomy 48 h after CLP) and spx + CLP (splenectomy surgery two weeks before CLP). Compared with the CLP mice, the CLP + spx and spx + CLP mice had improved survival rates and organ injuries, increased expression of inflammatory factors, a decreased proportion of regulatory T cells (Tregs), and reduced expression of the genes involved in the programmed cell death 1 and its ligand 1 (PD1-PDL1) pathway in immune cells and T-cell immunoglobulin-mucin domain 3 (Tim 3) and Galectin9 in the liver and lungs after 72 h in late-phase sepsis. In addition, the expression of PD-1 was significantly reduced in T cells in spx + CLP mice, and the expression of PD-L1 in myeloid-derived suppressor cells (MDSCs) was reduced in the CLP + spx group, especially in macrophages. These findings suggested that splenectomy could protect septic mice from exhaustion of immune cells by reducing the proliferation of Treg cells and expression of the PD-1/PD-L1 axis in immune cells during the immunosuppressive stage of sepsis. Splenectomy could also reduce liver and lung injuries possibly via the Tim 3 and/or Galectin-9 axis. The spleen is an important regulator of the occurrence and development of sepsis, which provides a new perspective to improve the prognosis of sepsis by regulating the spleen. [ABSTRACT FROM AUTHOR]

• 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]