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

Infectious complications determine the prognosis of cirrhosis patients. Their infection susceptibility relates to the development of immuneparesis, a complex interplay of different immunosuppressive cells and soluble factors. Mechanisms underlying the dynamics of immuneparesis of innate immunity remain inconclusive. We aimed to dissect the heterogeneity of circulating monocyte states in different cirrhosis stages, and pursued the function of selected differentially expressed genes. We systematically investigated circulating monocytes in health, compensated and not-acutely decompensated (NAD) cirrhosis using single cell RNA sequencing. Selective genes were confirmed by flow cytometry and diverse functional assays on monocytes ex vivo. We partitioned monocytes into seven clusters. Their abundances varied between cirrhosis stages, confirming previously reported changes i.e. reduction in CD14 CD16 and emergence of M-MDSC in advanced stages. DE genes between health and disease and among stages were detected, including for the first time CD52. CD52-expression on monocytes significantly enhanced throughout compensated and NAD cirrhosis. Heretofore the biological significance of CD52-expression on monocytes remained unknown. CD52 CD14 CD16 HLA-DR monocytes in patients with cirrhosis revealed a functional phenotype of active phagocytes with enhanced migratory potential, increased cytokine production, but poor T cell activation. Following acute decompensation (AD), CD52 was cleaved by elevated phospholipase C (PLC), and soluble CD52 (sCD52) was detected in the circulation. Inhibition and cleavage of CD52 significantly suppressed monocyte functions ex vivo and in vitro, and the predominance of immunosuppressive CD52 circulating monocytes in patients with AD was associated with infection and low transplant-free survival. 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 sCD52/PLC as biomarkers indicating immuneparesis. Monocyte dysfunction substantially contributes to infection susceptibility which determines the prognosis of cirrhosis patients, and represents a critical condition with unmet therapeutic needs. Its underlying mechanisms remain poorly understood, although among hepatologists a better understanding of the monocyte pathophysiology in relation to cirrhosis stages, and a therapeutic reconstitution of monocyte function are be