NK Cell Exhaustion in Wilson’s Disease Revealed by Single-cell RNA Sequencing Predicts the Prognosis of Cholecystitis

Metabolic abnormalities associated with liver disease have a significant impact on the risk and prognosis of cholecystitis. However, the underlying mechanism is complicated and remains to be elucidated. In particular, the effect of metabolic abnormalities on the progression of cholecystitis through the regulation of immune cell function is poorly understood. In this study, we investigated this issue using Wilson’s disease (WD) as a model. Wilson’s disease is a genetic disorder characterized by impaired mitochondrial function and abnormal copper metabolism. Our retrospective clinical study of over 600 patients with WD found that they have a significantly higher incidence of cholecystitis and a poorer prognosis. The immune cell landscape in the hepatic mesenchymal stromal microenvironment using single-cell RNA sequencing showed that the tissue immune microenvironment is altered in patients with WD, mainly a major change in the constitution and function of the innate immune system, including enhanced antigen presentation process, activation of immune response, and activation of lymphocytes. Exhaustion of natural killer (NK) cells is the fundamental factor, supported by an increase in the expression of the inhibitory receptors NKG2A and TIGIT and a decrease in the expression of cytotoxic molecules. Clinical tissue and blood samples verified increased NKG2A+ and TIGIT+ NK cells and decreased IFNγ+ NK cells in WD. Further bioinformatic analysis has confirmed a positive correlation between NK cell exhaustion and poor prognosis in cholecystitis and other inflammatory diseases. The study demonstrated abnormal function of liver mesenchymal immune cells triggered by specific metabolic dysfunction in WD, with a focus on the correlation between NK cell exhaustion and poor healing of cholecystitis. Our findings highlight the immune cell dysfunction due to hepatocytes metabolic changes, and provide new insights into improvement of inflammatory diseases by assessing immune cell function.