Chitinase 1: a novel therapeutic target in metabolic dysfunction-associated steatohepatitis

Front Immunol. 2024 Sep 23:15:1444100. doi: 10.3389/fimmu.2024.1444100. eCollection 2024.

Abstract

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by persistent inflammatory cascades, with macrophage activation playing a pivotal role. Chitinase 1 (CHIT1), produced by activated macrophages, is a key player in this cascade. In this study, we aimed to explore the role of CHIT1 in MASH with progressive liver fibrosis.

Methods: Fibrotic liver tissue and serum from distinct patient groups were analyzed using nCounter MAX, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. A MASH mouse model was constructed to evaluate the effectiveness of OATD-01, a chitinase inhibitor. Macrophage profiling was performed using single-nuclei RNA sequencing and flow cytometry.

Results: CHIT1 expression in fibrotic liver tissues was significantly correlated with the extent of liver fibrosis, macrophages, and inflammation. Single-nuclei RNA sequencing demonstrated a notable increase in macrophages numbers, particularly of lipid-associated macrophages, in MASH mice. Treatment with OATD-01 reduced non-alcoholic fatty liver disease activity score and Sirius red-positive area. Additionally, OATD-01-treated mice had lower CHIT1, F4/80, and α-smooth muscle actin positivity, as well as significantly lower levels of inflammatory markers, pro-fibrotic genes, and matrix remodeling-related mRNAs than vehicle-treated mice. Although the population of F4/80+CD11b+ intrahepatic mononuclear phagocytes remained unchanged, their infiltration and activation (CHIT1+MerTK+) significantly decreased in OATD-01-treated mice, compared with that observed in vehicle-treated mice.

Conclusions: Our study underscores the pivotal role of CHIT1 in MASH. The observed significant improvement in inflammation and hepatic fibrosis, particularly at higher doses of the CHIT1 inhibitor, strongly suggests the potential of CHIT1 as a therapeutic target in MASH accompanied by progressive liver fibrosis.

Keywords: MASH mouse mod; chitinase 1; inflammation; metabolic dysfunction-associated steatohepatitis; mononuclear phagocyte.

MeSH terms

  • Animals
  • Chitinases* / antagonists & inhibitors
  • Chitinases* / metabolism
  • Disease Models, Animal*
  • Female
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Macrophage Activation / drug effects
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism

Substances

  • Chitinases
  • CHIA protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00208767 to SB) and (RS-2024-00337298 to PS). This work was partly supported by the 2022 Leader Research Fund of Seoul St. Mary’s Hospital of the Catholic University of Korea (PS) and the Research Supporting Program of The Korean Association for the Study of the Liver and The Korean Liver Foundation (PS).