Latency-associated Peptide Degradation Fragments Produced in Stellate Cells and Phagocytosed by Macrophages in Bile Duct-ligated Mouse Liver

• Published in: The journal of histochemistry and cytochemistry Vol. 69; no. 11; pp. 723 - 730
• Main Authors: Inoue, Ikuyo, Qin, Xian-Yang, Masaki, Takahiro, Mezaki, Yoshihiro, Matsuura, Tomokazu, Kojima, Soichi, Furutani, Yutaka
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-11-2021
• Subjects: Animals; Bile Ducts - metabolism; Bile Ducts - pathology; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Latent TGF-beta Binding Proteins - metabolism; Liver - metabolism; Liver - pathology; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Inbred C57BL; Peptide Fragments - metabolism; TGF-β; liver fibrosis; LAP; plasma kallikrein
• ISSN: 0022-1554; 1551-5044
• DOI: 10.1369/00221554211053665

Transforming growth factor-β (TGF-β) activation is involved in various pathogeneses, such as fibrosis and malignancy. We previously showed that TGF-β was activated by serine protease plasma kallikrein-dependent digestion of latency-associated peptides (LAPs) and developed a method to detect LAP degradation products (LAP-DPs) in the liver and blood using specific monoclonal antibodies. Clinical studies have revealed that blood LAP-DPs are formed in the early stages of liver fibrosis. This study aimed to identify the cell source of LAP-DP formation during liver fibrosis. The N-terminals of LAP-DPs ending at residue Arg58 (R58) were stained in liver sections of a bile duct-ligated liver fibrosis model at 3 and 13 days. R58 LAP-DPs were detected in quiescent hepatic stellate cells at day 3 and in macrophages on day 13 after ligation of the bile duct. We then performed a detailed analysis of the axial localization of R58 signals in a single macrophage, visualized the cell membrane with the anti-CLEC4F antibody, and found R58 LAP-DPs surrounded by the membrane in phagocytosed debris that appeared to be dead cells. These findings suggest that in the early stages of liver fibrosis, TGF-β is activated on the membrane of stellate cells, and then the cells are phagocytosed after cell death: