The role of CD5L in regulating liver immune cells

CD5-like molecule (CD5L) is a soluble glycoprotein primarily produced and secreted by macrophages. As a member of the scavenger receptor cysteine-rich (SRCR) superfamily, CD5L regulates many biological processes such as apoptosis, pathogen recognition, immune responses, autophagy, cell polarization, and lipid metabolism, highlighting its crucial role in tissue homeostasis and its involvement in inflammation and cancer. In liver cancer, elevated serum CD5L levels have been observed in patients with steatohepatitis and hepatocellular carcinoma (HCC), supporting its potential as a diagnostic biomarker. Steatosis and steatohepatitis are key comorbidities that promote HCC development and are linked to poor therapeutic outcomes, particularly resistance to immune checkpoint inhibitors. Given that liver inflammation and lipid metabolism are involved in the progression of liver cancer, both of which are closely correlated with CD5L activity, this suggests that CD5L could play a pivotal role in shaping the tumor microenvironment of HCC. In this study, we found that CD5L is predominantly produced by liver macrophages and that its expression is significantly upregulated in multiple models of liver injury. Additionally, we observed that elevated serum CD5L levels were observed to correlated with the severity of liver damage. Clinically, we found that patients with hepatocellular carcinoma (HCC) displayed higher serum CD5L levels compared to controls, and increased CD5L levels were associated with poorer responses to immune checkpoint therapies. Functionally, we demonstrated that CD5L enhances lipid uptake in hepatocytes and hepatic stellate cells and promotes macrophage survival under palmitic acid-induced stress, findings consistent with its previously reported biological roles. Although CD5L's role in supporting macrophage survival is well established, its precise role in immune regulation remains less clearly defined. Our data indicate that CD5L produced by liver macrophages can modulate the chemotaxis of hepatic immune cells, particularly T cells and NKT cells. In macrophages and adipocytes, CD36, a scavenger receptor, mediates CD5L's effects on lipid metabolism. Notably, CD8+ T cells and regulatory T cells also express CD36, suggesting that CD5L may influence their function through CD36-dependent pathways. However, our findings show that while CD5L acts on T cells via CD36, it impacts NKT cells through a CD36-independent mechanism. Our study further investigates the impact of CD5L on liver immune cells' functional properties. Overall, CD5L is an upregulated secreted protein that plays an important role in regulating liver immune cells during liver diseases.