Circulating monocytes upregulate CD52 and sustain innate immune function in cirrhosis unless acute decompensation emerges

Background & Aims The susceptibility of patients with cirrhosis to infection, a major determinant of prognosis, relates to the development of immuneparesis, a complex interplay of different immunosuppressive cells and soluble factors. The mechanisms underlying the dynamics of immuneparesis of innate immunity remain unclear. We aimed to dissect the heterogeneity of circulating monocyte states in different stages of cirrhosis, and to determine the function of selected differentially expressed genes. Methods We systematically investigated circulating monocytes in health and compensated/non-acutely decompensated cirrhosis using single-cell RNA sequencing. Selective genes were confirmed by flow cytometry and diverse functional assays on monocytes ex vivo . Results We partitioned monocytes into seven clusters. Their abundances varied between cirrhosis stages, confirming previously reported changes, i.e. the reduction in CD14 low CD16 ++ and emergence of monocytic myeloid-derived suppressor cells in advanced stages. Differentially expressed genes between health and disease and among stages were detected, including CD52 for the first time. CD52 expression on monocytes significantly increased through compensated and non-acutely decompensated cirrhosis. In patients with cirrhosis, CD52 high CD14 + CD16 high HLA-DR high monocytes had a functional phenotype of active phagocytes, with enhanced migratory potential and increased cytokine production capacity but limited ability to activate T cells. Following acute decompensation, CD52 was cleaved by elevated PLC, and soluble CD52 was detected in the circulation. Inhibition and cleavage of CD52 significantly suppressed monocyte functions ex vivo and in vitro , while the predominance of immunosuppressive CD52 low circulating monocytes in patients with acute decompensation was associated with infection and low transplant-free survival. Conclusion CD52 may represent a biologically relevant target for future immunotherapy. Stabilising CD52 may enhance monocyte functions and infection control in the context of cirrhosis, guided by soluble CD52/PLC as biomarkers of immuneparesis. Impact and implications Monocyte dysfunction substantially contributes to infection susceptibility, which is a major determinant of the prognosis of patients with cirrhosis and represents a major unmet therapeutic need. Its underlying mechanisms remain poorly understood, although, among hepatologists, it is thought that the therapeutic reconstitution of monocyte function could enhance defence against infection and thus reduce morbidity and mortality of patients with cirrhosis. By systematically delineating the heterogeneity and function of circulating monocytes ex vivo , we identified that the absence of CD52 expression on monocytes represented a distinct biomarker of monocyte dysfunction in patients with cirrhosis, discriminating patients at substantial risk of infectious complications. Otherwise, given the beneficial antimicrobial functions of CD52-expressing monocytes, CD52 stablisation may also represent a therapeutic approach worth exploring.