Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice

Abstract

The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.

Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non‐alcoholic steatohepatitis mouse model

“…In this model, the reduction of liver damage was observed during the first week of treatment, and the reduction of liver damage and improvement of fibrosis was observed in the second week. In addition, single‐cell RNA analysis of hematopoietic cells showed that macrophages were the most affected cells in the liver tissue 4 weeks after treatment 10 . This peptide does not have a direct inhibitory effect on inflammatory factors in macrophages, and it indirectly affects macrophages in vivo.…”

“…In addition, single-cell RNA analysis of hematopoietic cells showed that macrophages were the most affected cells in the liver tissue 4 weeks after treatment. 10 This peptide does not have a direct inhibitory effect on inflammatory factors in macrophages, and it indirectly affects macrophages in vivo. This report indicates that HMBG1 has important antiinflammatory and fibrosis-improving properties, and we believe it is a new regeneration-inducing agent that can reduce damage and improve fibrosis in vivo.…”

“…4,5 Using this model, we evaluated the effects of mesenchymal stem cells (MSCs) and their exosomes on NASH, 6 the role of sphingosine-1-phosphate and their receptors, 7 the relationship between intestinal inflammation and the development of HCC, 8 and the therapeutic effects of ONO-1301. 9 Recently, we reported that HMGB1 peptide synthesized from box A of HMGB1 protein reduces liver damage and fibrosis in a mouse model of liver cirrhosis, 10 and we are conducting a physicianled clinical trial for cirrhosis. HMGB1 has two opposite roles, which can be induced by box A and box B.…”

Diagnostic and therapeutic strategies for non-alcoholic fatty liver disease

“…However, studies on drugs that increase fibrinolysis are lacking. A recent study shows that the HMGB one peptide can induce fibrinolysis ( Nojiri et al, 2021 ). Drugs targeting extracellular matrix deposition anti-fibrosis and their research progress are summarized in Table 4 .…”

PPARγ-dependent hepatic macrophage switching acts as a central hub for hUCMSCs-mediated alleviation of decompensated liver cirrhosis in rats

“…54 MSCs treatment restores liver macrophage homeostasis to ameliorates the progression of liver diseases including acute liver injury, liver brosis, and cirrhosis. [55][56][57] . Consistently, different hUCMSCs infusion regimens were found to exhibit differential effects on macrophage homeostasis regulation ability, among which the T-B group could signi cantly down-regulate the M1/M2 macrophages ratio.…”