Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice

Inflammation and Regeneration

Tomomi Kitayama¹  Yu-Tung Li¹  Yuya Ouchi¹  Takashi Shimbo¹  Katsuto Tamai¹  Masaaki Takamura²  Takeki Sato²  Hiroteru Kamimura²  Masahiro Ogawa²  Shunsuke Nojiri²  Takayuki Watanabe²  Masaru Kumagai²  Takahiro Iwasawa²  Shuji Terai²  Atsunori Tsuchiya²  Yui Ishii²  Kazuki Natsui²  Yuichi Kojima²  Suguru Takeuchi²  Satoko Motegi²  Yusuke Watanabe² 

[1] Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University;Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University;

关键词: HMGB1;    Peptide;    Liver;    Cirrhosis;    Fibrosis;    Mesenchymal stem cell;   

DOI  :  10.1186/s41232-021-00177-4

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown