Liver Fibrosis and Inflammation under the Control of ERK2

Abstract

Chronic liver injury could lead the formation of liver fibrosis, eventually some would develop to hepatocellular carcinoma (HCC), one of the leading malignancies worldwide. The aim of the study is to dissect the role of extracellular signal-regulated kinase 2 (ERK2) signaling in liver fibrosis and inflammation. The choline-deficient, ethionine-supplemented (CDE) diet could lead to fatty livers and generate oval cells, activate hepatocyte stellate cell (HSC) and recruit immune cells as the liver fibrosis model mice. WT and ERK2 deficient (ERK2−/−) mice were compared in terms of liver weight/body weight, liver function, liver fibrosis markers and the differential gene expression in hepatotoxicity. ERK2−/− mice display the less degree of liver fibrosis when compared to WT mice. The protein level of alpha smooth muscle (α-SMA) was reduced and several hepatocellular carcinoma-related genes such as MMP9, FoxM1 were down-regulated. In addition, the cell proliferation and the percentages of activated T cells were reduced in ERK2−/− mice upon liver injury. Therefore, ERK2 plays an important role in regulating liver cirrhosis and inflammation.

Role of Cytokines on the Progression of Liver Fibrosis in Mice Infected with Echinococcus multilocularis

“…Liver fibrosis, as one of the histopathological phenomena in mice infected with E. multilocularis , is associated with aberrant apoptosis of hepatocytes, collagen formation and liver immune cells inflammation. 4 Interactions between HSCs, liver resident immune cells, hepatocytes and/or sinusoidal endothelial cells, which constitute the liver microenvironment, are crucial not only for host defense but also for tissue remodeling. 9 The cross-talk between HSCs and immune cells in the hepatic microenvironment during liver pathophysiology is crucial for ECM deposition and fibrosis development.…”

“…Liver fibrosis, as one of the histopathological phenomena in mice infected with E. multilocularis , is associated with aberrant apoptosis of hepatocytes, collagen formation and liver immune cells inflammation. 4 In chronic and persistent inflammatory injuries, such as alcoholic hepatitis, viral hepatitis, parasitic diseases, and so on, this abnormal regulation of liver tissue repair mechanisms leads to irreversible fibrosis, more seriously, liver cirrhosis or liver cancer. Parasite stimulation triggers the rapid recruitment of immune cells, such as neutrophils and macrophages.…”

TGF‐β as a driver of fibrosis: physiological roles and therapeutic opportunities

“…However, while these studies inform us about contributions of the individual pathways to fibrosis, they are not necessarily informative about their roles in direct responses to TGF‐β, since diverse stimuli, most notably growth factors that activate receptor tyrosine kinases, also upregulate these pathways in fibrosis [143–145]. Among the MAPK pathways, the MEK1/2–Erk MAPK pathway contributes to fibrosis in several mouse models [146–148], and p38 MAPK also contributes to renal and cardiac fibroses [149–153].…”

Familiarity Breeds Strategy: In Silico Untangling of the Molecular Complexity on Course of Autoimmune Liver Disease-to-Hepatocellular Carcinoma Transition Predicts Novel Transcriptional Signatures

“…For example, the pro-inflammatory signaling events such as ERK/MAPK pathway, TLR cascades operating downstream of cluster 1 transcriptional modules have been shown to be active during the early fibrotic stages. Erk2 -/mice displayed reduced level of liver fibrosis, decreased cell proliferation rate and aggravated immunosuppression in response to fibrosis-inducing diet [46], whereas liver-specific TRAF6 overexpression restored fibrosis in Traf6 +/− mice, which normally showed compromised fibrosis [47]. On the other hand, lipid metabolic processes regulated by cluster 3 transcriptional modules have been proven to go downhill on course of liver fibrosis.…”