2. Academic Validation
  3. Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

  • Cell Death Dis. 2021 Dec 1;12(12):1123. doi: 10.1038/s41419-021-04403-2.
Xuejiao Chen  # 1 2 3,  Ziyi Wang  # 1 2 3,  Sheng Han  # 1 2 3,  Zeng Wang 1 2 3,  Yu Zhang 1 2 3,  Xiangdong Li 1 2 3,  Nan Xia 1 2 3,  Wenjie Yu 1 2 3,  Chenyang Jia 4,  Yong Ni 5,  Liyong Pu 6 7 8
Affiliations

Affiliations

  • 1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2 Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
  • 3 NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
  • 4 Department of Hepatopancreatobiliary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China.
  • 5 Department of Hepatopancreatobiliary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China. niyong123456@163.com.
  • 6 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. puliyong@njmu.edu.cn.
  • 7 Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. puliyong@njmu.edu.cn.
  • 8 NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China. puliyong@njmu.edu.cn.
  • # Contributed equally.
PMID: 34853322 DOI: 10.1038/s41419-021-04403-2
Abstract

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. 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. 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. We have evaluated the ability of the small molecule Syk Inhibitor GS9973 in a variety of models. 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. 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. 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15947
    99.75%, ERK抑制剂
    ERK
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