Spleen tyrosine kinase (SYK) is a 72 kDa non-receptor tyrosine kinase that plays a multiple roles in human immune response. Ishak score (Ishak0–6) is commonly used clinically to classify the severity of liver fibrosis. The diagnosis methods of liver fibrosis include invasive and non-invasive, but pathological biopsy is still the gold standard. Liver fibrosis progresses to liver cirrhosis and thus becomes an important risk factor for the progression of liver cancer. Repeated chronic damage to the liver stimulates hepatic stellate cells (HSC) to synthesize and accumulate excessive extracellular matrix. The main causes of liver fibrosis are viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver. Liver fibrosis is a chronic liver disease characterized by chronic tissue damage and the accumulation of extracellular protein matrix. Our further findings indicate that on the basis of the administration of CCR2/CCR5 dual inhibitor Cenicriviroc, further inhibiting MoMFs SYK may give patients with fibrosis additional benefits. In addition, we found that inhibition of MoMFs SYK impairs the expression of CXCL1, on one hand, it reduces the recruitment of CD11bhiLy6Chi inflammatory cells, and on the other hand, it promotes the phenotype cross-dress process of pro-resolution MoMFs, thereby remodeling the chronic inflammatory environment of the fibrotic liver. Contrary to previous impressions, high-frequency administration of GS9973 will aggravate CCL4-induced liver fibrosis, which is especially unsuitable for patients with cholestasis whose clinical features are bile duct obstruction. We have evaluated the ability of the small molecule SYK inhibitor GS9973 in a variety of models.
Our studies based on chronic CCL4, bile duct ligation, and subacute TAA mouse models show that SYK in monocyte-derived macrophages (MoMFs) is fully dependent on phosphorylation of Erk to up-regulate the expression of Hif1α, thereby forming the crosstalk with SYK to drive liver fibrosis progress.
Although a variety of drugs targeting SYK have been developed for tumors and autoimmune diseases, the mechanism and specific efficacy of SYK’s role in liver fibrosis are not yet clear. Liver fibrosis is a danger signal indicating a huge risk of liver cancer occurrence, but there is still no effective clinical means to regulate the progress of liver fibrosis.
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