Inhibition of macrophages inflammasome activation via autophagic degradation of HMGB1 by EGCG ameliorates HBV-induced liver injury and fibrosis

Abstract

BackgroundLiver fibrosis is a reversible wound-healing response that can lead to end-stage liver diseases without effective treatment, in which HBV infection is a major cause. However, the underlying mechanisms for the development of HBV-induced fibrosis remains elusive, and efficacious therapies for this disease are still lacking. In present investigation, we investigated the effect and mechanism of green tea polyphenol epigallocatechin-3-gallate (EGCG) on HBV-induced liver injury and fibrosis.MethodsThe effect of EGCG on liver fibrosis was examined in a recombinant cccDNA (rcccDNA) chronic HBV mouse model by immunohistochemical staining, Sirius red and Masson’s trichrome staining. The functional relevance between high mobility group box 1 (HMGB1) and inflammasome activation and the role of EGCG in it were analyzed by Western blotting. The effect of EGCG on autophagic flux was determined by Western blotting and flow cytometric analysis.ResultsEGCG treatment efficiently was found to alleviate HBV-induced liver injury and fibrosis in a recombinant cccDNA (rcccDNA) chronic HBV mouse model, a proven suitable research platform for HBV-induced fibrosis. Mechanistically, EGCG was revealed to repress the activation of macrophage NLRP3 inflammasome, a critical trigger of HBV-induced liver fibrosis. Further study revealed that EGCG suppressed macrophage inflammasome through downregulating the level of extracellular HMGB1. Furthermore, our data demonstrated that EGCG treatment downregulated the levels of extracellular HMGB1 through activating autophagic degradation of cytoplasmic HMGB1 in hepatocytes. Accordingly, autophagy blockade was revealed to significantly reverse EGCG-mediated inhibition on extracellular HMGB1-activated macrophage inflammasome and thus suppress the therapeutic effect of EGCG on HBV-induced liver injury and fibrosis.ConclusionEGCG ameliorates HBV-induced liver injury and fibrosis via autophagic degradation of cytoplasmic HMGB1 and the subsequent suppression of macrophage inflammasome activation. These data provided a new pathogenic mechanism for HBV-induced liver fibrosis involving the extracellular HMGB1-mediated macrophage inflammasome activation, and also suggested EGCG administration as a promising therapeutic strategy for this disease.

Castanopsis sieboldii Extract Alleviates Acute Liver Injury by Antagonizing Inflammasome-Mediated Pyroptosis

“…It has been reported that EGCG prevents liver inflammation, oxidative stress, and even fibrosis in CCl4-induced liver injury in mice [41]. EGCG treatment suppressed NLRP3 inflammasome in Kupffer cells, which resulted in the therapeutic effect of EGCG against HBV-induced liver injury [42]. Therefore, we speculated that the anti-inflammatory and hepatoprotective effects of CSL3 are due to EGCG.…”

Macrophages and platelets in liver fibrosis and hepatocellular carcinoma

“…For example, complement factor C5a stimulates pro-inflammatory pathways via C5aR1 on macrophages, and C5aR1ko knockout mice showed a M1- to M2-type macrophage transition and reduced fibrosis in a MASH mouse model ( 122 ). HMBG1 secretion from injured hepatocytes induced NLRP3 inflammasome activation in macrophages ( 123 ), and fibrinogen-like protein 2 (Fgl2), which was upregulated in liver tissues of cirrhotic patients with underlying hepatitis C infection, promoted M1 polarization ( 124 ). Furthermore, autophagy triggered a M2-type, whereas LPS stimulation favored a M1-type macrophage polarization and blocked autophagy ( 125 ).…”

Aging aggravates liver fibrosis through downregulated hepatocyte SIRT1-induced liver sinusoidal endothelial cell dysfunction

“… 17 Downregulation of SIRT1 in senescent hepatocytes reportedly exacerbates carbon tetrachloride (CCl 4 )-induced and alcohol-induced liver injury and fibrosis in aged mice 4 , 5 ; however, whether HMGB1 is involved in this process is unknown. In addition, HMGB1 is primarily secreted by damaged hepatocytes in CLD, 18 and current studies mostly concentrate on how extracellular HMGB1 activates HSCs in liver fibrosis. 19 However, the effects of HMGB1 on other hepatic nonparenchymal cells and the role of circulating HMGB1 are partially understood.…”