MMP10 alleviates non-alcoholic steatohepatitis by regulating macrophage M2 polarization.

BACKGROUND: Non-alcoholic steatohepatitis (NASH), the most severe form of non-alcoholic fatty liver disease (NAFLD), is currently untreatable with a clinically validated treatment. Matrix Metallopeptidase 10 (MMP10) is a common host-response-gene involved in the immune response. However, it remains unknown whether and how MMP10 influences NASH development by modulating macrophage function. METHODS: In vitro, MMP10 overexpression (MMP10-OE), MMP10 knockout (MMP10-KO), proliferator-activated receptor γ (PPARγ)-OE, and control plasmids were transfected into primary Kupffer cells, which were then cultured with or without Interleukin (IL)-4 stimulation. MMP10-OE mice and MMP10-KO mice were fed a normal chow diet (NCD) or a high-fat diet (HFD) for 30 weeks to study the role of MMP10 in NASH model. Hepa1-6 cells were cultured with or without free fatty acid (FFA) treatment for 24 h. RESULTS: MMP10 is downregulated in NASH, and M1/M2 indicators are significantly imbalanced. MMP10 is triggered in response to M2 macrophages polarization. MMP10 overexpression diminishes hepatic steatosis and inflammation in HFD-induced NASH. Mechanistically, PPARγ can bind to the MMP10 promoter and then up-regulates MMP10 expression, which is engaged when IL-4 stimulates M2 macrophage polarization. The downstream STAT3 signaling pathway is further activated to induce M2 polarization, which results in a decreased expression of the pro-inflammatory IL-1ß and tumor necrosis factor (TNF)-a and an increased expression of the anti-inflammatory IL-10, ultimately alleviating NASH progression. CONCLUSIONS: We demonstrate that IL-4 effectively promotes MMP10 expression via PPARγ, and MMP10 overexpression modulates macrophage polarization, hepatic steatosis, and fibrosis, offering prospective targets for NASH treatment.

Research progress on hepatic machine perfusion.

Nowadays, liver transplantation is the most effective treatment for end-stage liver disease. However, the increasing imbalance between growing demand for liver transplantation and the shortage of donor pool restricts the development of liver transplantation. How to expand the donor pool is a significant problem to be solved clinically. Many doctors have devoted themselves to marginal grafting, which introduces livers with barely passable quality but a high risk of transplant failure into the donor pool. However, existing common methods of preserving marginal grafts lead to both high risk of postoperative complications and high mortality. The application of machine perfusion allows surgeons to make marginal livers meet the standard criteria for transplant, which shows promising prospect in preserving and repairing donor livers and improving ischemia reperfusion injury. This review summarizes the progress of recent researches on hepatic machine perfusion.