Abstract

Background & AimsInfectious 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 (DE) genes. MethodsWe 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. ResultsWe identified seven monocyte clusters. Their abundances varied between cirrhosis stages, confirming previously reported changes i.e. reduction in CD14lowCD16++ 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. CD52highCD14+CD16highHLA-DRhigh 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 CD52low circulating monocytes in patients with AD was associated with infection and low transplant-free survival. ConclusionCD52 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. Lay summaryRecurrent infections are a major cause of death in patients with liver cirrhosis. A fundamental understanding of the mechanisms that suppress immune responses in patients with cirrhosis is lacking, but required for the development of strategies to restore innate immunity in cirrhosis patients and prevent infection. The current study identified a novel marker for deficient immune responses and a potential target for such a future immune-based therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/587894v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1a42b1borg.highwire.dtl.DTLVardef@10a0df2org.highwire.dtl.DTLVardef@1199087org.highwire.dtl.DTLVardef@15fb074_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO scRNA-seq identified seven circulating monocyte states, changing in cirrhosis patients at different stages of disease. Circulating monocytes overexpress CD52 in cirrhosis, but are absent in AD/ACLF due to PLC. CD52-expressing monocytes show high capability for phagocytosis, cytokine production, adhesion and migration potential and T cell suppression. Created with BioRender.com C_FIG