Distinct circulating monocytes up-regulate CD52 and sustain innate immune function in patients with cirrhosis unless acute decompensation emerges
Authors: Geng Anne , Brenig Robert G. , Roux Julien , Lütge Mechthild , Cheng Hung-Wei , Flint Emilio , Meier Marie-Anne , Pop Oltin T. , Künzler-Heule Patrizia , McPhail Mark J. W. , Soysal Savas , Semela David , Heim Markus , Weston Chris J. , Ludewig Burkhard , Bernsmeier Christine 
Published: April 2024

Background & Aims

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 (DE) genes.

Methods

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 monocytesex vivo.

Results

We 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-DRhighmonocytes 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 functionsex vivoandin vitro, and the predominance of immunosuppressive CD52lowcirculating monocytes in patients with AD 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 sCD52/PLC as biomarkers indicating immuneparesis.

Lay summary

Recurrent 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.

Abstract Figure

Graphical Abstract

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 withBioRender.com