ABSTRACT
Alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), two main types of steatotic liver disease (SLDs), are characterized by a wide spectrum of several different liver disorders, including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Multiple immune cell-mediated inflammatory responses not only orchestrate the killing and removal of infected/damaged cells but also exacerbate the development of SLDs when excessive or persistent inflammation occurs. In recent years, single-cell and spatial transcriptome analyses have revealed the heterogeneity of liver-infiltrated immune cells in ALD and MASLD, revealing a new immunopathological picture of SLDs. In this review, we will emphasize the roles of several key immune cells in the pathogenesis of ALD and MASLD and discuss inflammation-based approaches for effective SLD intervention. In conclusion, the study of immunological mechanisms, especially highly specific immune cell population functions, may provide novel therapeutic opportunities for this life-threatening disease.
ABSTRACT
Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.
