Extracellular calreticulin regulates fibrogenic and immunogenic properties of hepatic stellate cells

Liver fibrosis is a persistent damage repair response triggered by various etiological factors, resulting in an excessive accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HpSCs) are the primary source of ECM proteins. Therefore, specifically targeting HpSCs has become a crucial approach for treating liver fibrosis. Calreticulin (CRT) is a molecular chaperone mainly located in the endoplasmic reticulum (ER), regulating protein folding and calcium homeostasis. Recently, CRT has gained much attention for its role outside the ER, particularly at the cell surface and extracellular space, acting as an immunomodulatory protein. The current study investigates the role of extracellular CRT in hepatic injury and its effects on HpSCs. Elevated levels of circulating CRT were observed in mouse models of liver injury, suggesting that hepatic injury may trigger CRT release. Extracellular CRT was found to moderately inhibit HpSC viability and induce morphological changes. Additionally, CRT treatment led to a decrease in α-smooth muscle actin and an upregulation of matrix metalloproteinase-2 and -9, indicating a potential fibrolytic effect. Immunomodulatory activities of CRT were also noted, as it increased cytokine expression in both macrophages and HpSCs. These effects were partially mediated through low-density lipoprotein receptor-related protein 1 (LRP1), as evidenced by altered cytokine expression upon co-treatment with a known LRP1 ligand receptor-associated protein (RAP). Overall, this study elucidates the complex role of extracellular CRT in liver injury and its potential impact on HpSC behavior and immune responses.