Activation of MEK-ERK-c-MYC signaling pathway promotes splenic M2 macrophage polarization to inhibit PHcH-liver cirrhosis

Portal hypertension combined with hypersplenism (PHcH) is the main cause of hypocytosis and esophagogastric variceal hemorrhage in patients with liver cirrhosis. Activated macrophages that destroy excess blood cells are the main cause of hypersplenism, but the activating pathway is not very clear. This study aims to investigate the activation types of splenic macrophages and their activation mechanisms, to provide experimental evidence for the biological treatment of splenomegaly, and aiming to find a strategy to improve liver fibrosis and inflammation by intervening in splenic immune cells. This study revealed the occurrence of M2 type polarization of macrophages and upregulation of c-Myc gene expression in the PH spleen. RNAseq, protein chip, western blot, and chip-seq were performed on macrophages and the in vitro MEK inhibitor rafametinib was used. Carbon tetrachloride and thioacetamide induced mouse cirrhosis models were separately constructed. c-Myc gene knockout in splenic macrophages reduced M2 type polarization and exacerbated liver fibrosis inflammation. c-Myc activated the MAPK signaling pathway and upregulated the expression of IL-4 and M2 related genes in PH hypersplenism through the MEK-ERK-c-Myc axis. In addition, the c-Myc gene exerted anti-inflammatory effects by upregulating IL-4-mediated signal transduction to promote M2 type differentiation and anti-inflammatory cytokine secretion. Therefore, the induction of macrophage depolarization might represent a new therapeutic approach in the cure of PH hypersplenism, making c-Myc a potential candidate for macrophage polarization therapy. Overall design: Fresh human normal spleen samples (n = 15) were obtained from patients with traumatic splenic rupture who underwent splenectomy (Nor group); splenic samples (n = 36) of hepatitis B cirrhosis, accompanied by PH were obtained from patients with PH hypersplenism who underwent splenectomy (PH group).Study on the mechanism of C-myc gene involvement in M2 macrophage regulation in patients with PH splenomegaly . This study primers macrophage specific C-Myc KO mice and constructs two liver fibrosis models, CCL4 and TAA, to verify the polarization characteristics and specific mechanism changes of mouse spleen macrophages after C-Myc gene KO. mether: qPCR?WB?IHC?FACS?RNAseq, protein chip, western blot, and chip-seq were performed on macrophages and the in vitro MEK inhibitor rafametinib