Chang Na, Ma Yuehan, Liu Jing, Li Weiyang, Zhao Jing, Liu Yuran, Liu Fuquan, Dong Chengbin, Liu Chang, Qi Changbo, Yang Lin, Li Liying
Department of Cell Biology, Laboratory for Clinical Medicine, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, No.10 Xitoutiao You An Men, Beijing, 100069, China.
Department of Interventional Therapy, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
J Mol Med (Berl). 2025 Jul 19. doi: 10.1007/s00109-025-02573-6.
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 (CCl), 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) dependent manner. S1P/S1PR 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.
含IQ模体的GTP酶激活蛋白1（IQGAP1）是一种支架蛋白，与细胞迁移有关。我们之前的研究表明，1-磷酸鞘氨醇（S1P）可诱导骨髓来源的巨噬细胞（BMDM）募集，并促进慢性肝脏炎症/纤维化。然而，IQGAP1在S1P诱导的BMDM迁移和肝脏炎症/纤维化中的作用仍不清楚。通过四氯化碳（CCl）、胆管结扎（BDL）或蛋氨酸-胆碱缺乏高脂（MCDHF）饮食诱导小鼠肝纤维化。采用免疫荧光和单细胞RNA测序研究IQGAP1在纤维化肝脏中的表达。使用IQGAP1 siRNA-GeRPs在巨噬细胞中选择性敲低IQGAP1表达。采用RT-qPCR和蛋白质印迹法评估基因表达。采用Boyden小室试验分析体外BMDM迁移。IQGAP1表达显著升高，在人类或小鼠纤维化肝脏中由肝巨噬细胞高表达，且与炎症标志物表达呈正相关。在体内，巨噬细胞中IQGAP1的选择性敲低有效减轻了小鼠肝脏炎症/纤维化。在体外，S1P处理的BMDM中增加的IQGAP1参与了S1P诱导的BMDM迁移。S1P以依赖S1P受体2/3（S1PR）的方式上调IQGAP1表达。S1P/S1PR通过上调RNA结合蛋白Hu抗原R（HuR）的表达来调节IQGAP向1表达。进一步研究表明，被S1P下调的miR-455-5p也参与了IQGAP1的表达和BMDM迁移。总之，IQGAP1在S1P诱导的BMDM迁移和肝脏炎症/纤维化中起关键作用，为IQGAP1对慢性肝脏炎症/纤维化的作用提供了新的见解。
