Myeloid Glutamine Synthetase Protects Against Acute Liver Injury in Mice Independent of Its Enzyme Activity

作者：Jianghong Yu, Menglin Shi, Yumeng Guo, K. S. Fu, Jun Zhang, Hao Ding, Mengxiao Ge, Shuangyi Sun, Huilu Zhang, Jie Liu · 发表于：Liver International · 年份：2025 · DOI：10.1111/liv.70105 · 被引用次数：2 · 研究领域：Clinical Nutrition and Gastroenterology、Cancer, Hypoxia, and Metabolism、Liver Disease and Transplantation

ABSTRACT Background Glutamine synthetase (GS, encoded by Glul ) is a well‐known ammonia‐detoxifying enzyme, but its function in acute liver injury (ALI) remains unclear. Methods Lipopolysaccharide (LPS) and D‐galactosamine (D‐GalN) were utilised to construct the murine ALI model. C57BL/6J‐Glul em1(flox)Smoc mice ( Glul f/f ) and B6.129‐Lyz2 tm1(cre)smoc ( Lyz2‐Cre ) transgenic mice were crossed to generate Lyz2 + Glul f/f ( Glul ∆Lyz2 ) mice with a selectively knockout of Glul in myeloid cells. Histological staining experiments were performed to evaluate liver injury. Flow cytometry and RNA sequencing analyses were conducted to investigate the effects of Glul deficiency on liver immunity. Additionally, several strategies were applied to intervene ALI in mice, including administration of CCL2 neutralising antibody or GS inhibitor L‐methionine sulfoximine (MSO), as well as adeno‐associated virus (AAV)‐mediated enhancement of GS expression. Results The expression of Glul in myeloid cells was downregulated in wild‐type mice after ALI modelling by LPS/D‐GalN. Moreover, Glul ∆Lyz2 mice demonstrated aggravated ALI and higher mortality upon LPS/D‐GalN challenge, compared to the control Glul f/f littermates. Notably, Glul deficiency significantly contributed to the activation of monocyte‐derived macrophages (MoMFs), secretion of C‐C chemokine ligand 2 (CCL2) and the recruitment of C‐C chemokine receptor 2‐positive monocytes. Treatment with CCL2 neutralising antibody significantly alle...