MSR1-dependent efferocytosis improved ischemia-reperfusion injury following aged-donor liver transplantation in mice by regulating the pro-resolving polarisation of macrophages

• Published in: Experimental cell research 2024-09, Vol.442 (1), p.114212, Article 114212
• Main Authors: Xu, Xue-song, Liu, Tao, Chen, Ya-jun, Wu, Xin-yi, Cheng, Ming-xiang, Li, Jin-zheng
• Format: Article
• Language: English
• Subjects: Aged-donor liver transplantation; Animals; Efferocytosis; Glycogen Synthase Kinase 3 beta - metabolism; Ischemia-reperfusion injury; Liver - metabolism; Liver - pathology; Liver Transplantation - adverse effects; Liver Transplantation - methods; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; MSR1; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; Pro-resolving polarisation; Proto-Oncogene Proteins c-akt - metabolism; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - metabolism; Signal Transduction; Tissue Donors
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2024.114212

Compared with young liver donors, aged liver donors are more susceptible to ischemia-reperfusion injury (IRI) following transplantation, which may be related to excessive inflammatory response and macrophage dysfunction, but the specific mechanism is unclear. Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, and plays an important regulatory role in inflammation response and macrophage function regulation. But its role in IRI following aged-donor liver transplantation is still unclear. This study demonstrates that MSR1 expression is decreased in macrophages from aged donor livers, inhibiting their efferocytosis and pro-resolving polarisation. Decreased MSR1 is responsible for the more severe IRI suffered by aged donor livers. Overexpression of MSR1 using F4/80-labelled AAV9 improved intrahepatic macrophage efferocytosis and promoted pro-resolving polarisation, ultimately ameliorating IRI following aged-donor liver transplantation. In vitro co-culture experiments further showed that overexpression of MSR1 promoted an increase in calcium concentration, which further activated the PI3K-AKT-GSK3β pathway, and induced the upregulation of β-catenin. Overall, MSR1-dependent efferocytosis promoted the pro-resolving polarisation of macrophages through the PI3K-AKT-GSK3β pathway-induced up-regulating of β-catenin leading to improved IRI following aged-donor liver transplantation. Upregulation of MSR1 expression in liver macrophages to enhance efferocytosis, by increasing intracellular calcium ions, activating the PI3K-AKT-GSK3β signaling pathway, reducing β-catenin degradation, and ultimately promoting the pro-resolving polarisation of macrophages, improves the delayed recovery period of ischemia-reperfusion injury after elderly liver transplantation. [Display omitted]