Macrophage-derived CCL1 targets CCR8 receptor in hepatic stellate cells to promote liver fibrosis through JAk/STAT pathway

• Published in: Biochemical pharmacology Vol. 237; p. 116884
• Main Authors: Diao, Shaoxi, Li, Liangyun, Zhang, Jintong, Ji, Minglu, Sun, Lijiao, Shen, Wenwen, Wu, Shuai, Chen, Zixiang, Huang, Cheng, Li, Jun
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.07.2025
• Subjects: Animals; Apoptosis; C-C motif chemokine ligand 1; C-C motif chemokine receptor 8; Chemokine CCL1 - metabolism; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Humans; JAK/STAT pathway; Janus Kinases - metabolism; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver fibrosis; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Receptors, CCR8 - genetics; Receptors, CCR8 - metabolism; Signal Transduction - physiology; STAT Transcription Factors - metabolism; C-C motif chemokine ligand 1; DMSO; JAK/STAT pathway; ALT; ddH2O; Liver fibrosis; LPS; BSA; DMEM; α-SMA; 7-AAD; min; FBS; CCR8; HSC; CCL1; cDNA; TEMED; RT-qPCR; PBS; AST; SDS; TBS; IL-4; TBST; siRNA; DEPC; M−CSF; EDTA; IL-1β; NASH; PVDF; COL.I; ECM; rpm; PMSF; HBSS; C-C motif chemokine receptor 8; mL; Apoptosis
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2025.116884

[Display omitted] Liver fibrosis is caused by liver injury resulting from the wound healing response. According to recent research, the primary factor responsible for liver fibrosis is the activation of hepatic stellate cells (HSCs). C-C motif chemokine ligand 1 (CCL1) is one of several chemokine genes clustered on chromosome 17, which is involved in immune regulation and inflammatory processes. However, the role of CCL1 in liver fibrosis has not been reported. We found that CCL1 secreted by macrophages can target and activate the receptor protein C-C motif chemokine receptor 8 (CCR8) of HSCs, accelerating liver fibrosis progression by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. This suggested that the CCL1-mediated regulation of CCR8 is an important event in liver fibrosis progression. In conclusion, this study identified a novel signalling axis, the CCL1/CCR8/JAK/STAT pathway, which regulates the activation and apoptosis of HSCs, thus providing a novel therapeutic strategy for liver fibrosis.