IQGAP1 participates in bone marrow-derived macrophage recruitment and involves in liver inflammation/fibrosis.

Abstract

IQ motif containing GTPase activating protein 1 (IQGAP1), a scaffold protein, is implicated in cell migration. Our previous studies demonstrate that sphingosine 1-phosphate (S1P) induces bone marrow-derived macrophages (BMDMs) recruitment and promotes chronic liver inflammation/fibrosis. However, the role of IQGAP1 in S1P-induced BMDM migration and liver inflammation/fibrosis remains unclear. Mouse liver fibrosis was induced by carbon tetrachloride (CCl₄), bile duct ligation (BDL) or methionine-choline-deficient and high-fat (MCDHF) diet. Immunofluorescence and single-cell RNA sequencing were employed to study the expression of IQGAP1 in fibrotic liver. Selective knockdown of IQGAP1 expression in macrophages was performed using IQGAP1 siRNA-GeRPs. RT-qPCR and western blot were used to assess gene expression. The Boyden chamber assay was employed to analyze BMDM migration in vitro. IQGAP1, with significantly elevated expression, was highly expressed by hepatic macrophages and positively related with inflammatory marker expression in human or mouse fibrotic livers. In vivo, selective knockdown of IQGAP1 in macrophages effectively alleviated mouse liver inflammation/fibrosis. In vitro, IQGAP1, which was increased in S1P-treated BMDMs, participated in S1P-induced BMDM migration. S1P up-regulated IQGAP1 expression in a S1P receptor 2/3 (S1PR_2/3) dependent manner. S1P/S1PR_2/3 regulated IQGAP1 expression via up-regulating RNA binding protein Hu antigen R (HuR) expression. Further studies demonstrated that miR-455-5p, which was down-regulated by S1P, was also involved in IQGAP1 expression and BMDM migration. In conclusion, IQGAP1 plays a crucial role in S1P-induced BMDM migration and liver inflammation/fibrosis, providing new insight into the contribution of IQGAP1 to chronic liver inflammation/fibrosis.