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Human monocytes exhibit a functional and transcriptional reprogramming during Acute-on-Chronic-Liver-Failure with a key role for IL-10

ABSTRACT: Background and aims: Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function and organ failure, whereby immunoparesis and susceptibility to infections often precipitate this syndrome. Here we characterized the events triggering immune dysfunction in monocytes within alcoholic liver disease. Methods: We evaluated the frequency of monocyte subsets, their intracellular IL10 production, surface HLA-DR expression, and phagocytic and oxidative burst capacity in patients with decompensated cirrhosis, -alcoholic hepatitis or ACLF. RNAsequencing of ACLF patient-derived CD14+ monocytes were performed either immediately or after 12-hour culture in the presence or absence of plasma from ACLF patients. In this in vitro model of ACLF induction in CD14+ monocytes we characterized the early molecular, immunological and functional changes. Results: Besides a redistribution of monocyte subset composition, ACLF patient-derived monocytes featured elevated frequencies of IL-10-producing cells, reduced HLA-DR expression and impaired phagocytic- and oxidative burst capacity. RNAsequencing revealed a reprogramming of ACLF monocytes, whereby they undergo a transition from a pro-inflammatory to an immunosuppressive- and altered metabolic status. Culturing healthy monocytes in the presence of ACLF plasma, blunted their phagocytic capacity and triggered a gene expression pattern comparable to ACLF patients. Conversely, culturing patient monocytes in normal plasma restored their phagocytic capacity. Finally, plasma IL-10 levels correlated with patient survival. Conclusion: ACLF monocytes featured a defective immunosuppressive and -glycolytic profile, an attribute which could be mimicked by culturing healthy monocytes in the presence of ACLF patient plasma. Our data implicate a role for IL-10 signaling pathways in triggering monocytes dysfunction and opens up new avenues for therapeutic targeting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93265 | GEO | 2019/02/06

REPOSITORIES: GEO

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Project description:The malignancy potential is correlated with mechanical deformability of the cancer cells. Therefore, mechanical properties of individual patient cells can contribute essential knowledge in cancer diagnostics and in precision therapies. However, clinical applications are limited by lack of current knowledge and of reliable and robust cell mechanical tests. In a comprehensive study, we found a Triangular Correlation (TrC) between cell deformability, phagocytic like capacity, and cancer aggressiveness. A significant application of the TrC is that phagocytic measurements can be a surrogate marker for detecting malignancy of cancer cells based on mechanical properties. We found that the uptake of inert sub-micron and micro-beads was massively higher in cancer cells compared with non-cancerous cells. Moreover, cells with a higher malignancy potential had greater uptake capacity. Importantly, in a reciprocal approach, we sorted either human bladder cancer cells or melanoma cells into subpopulations, solely based on their phagocytic capacity. The more phagocytic subpopulations showed elevated phenotypes of cancer aggressiveness ex vivo and in vivo. The uptake potential was found to be an imprinted feature preserved genetically and enriched over the sorting cycles. A gene expression profile revealed differences in gene sets associated with regulation of cell-cell and extracellular matrix adhesions and epithelial-to-mesenchymal transition. Chromatin immunoprecipitation sequencing showed that differences in gene expression were reflected also at the chromatin level. Importantly, in all cases studied here, enhanced phagocytic ability and elevated aggressiveness phenotypes were correlated with greater cell deformability, providing the mechanical link of the TrC. A computational model supported the notion that the uptake capacity can be a marker for malignancy mediated by cell mechanics. Our multidisciplinary approach, which involved complementary directions of study in several types of cancer cells, provides the proof of concept that phagocytic measurements can be applied for cancer diagnostics and precision medicine.

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Human monocytes exhibit a functional and transcriptional reprogramming during Acute-on-Chronic-Liver-Failure with a key role for IL-10

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