Abstract
Background and AimsLiver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence.MethodsPeripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry.ResultsThe selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment.ConclusionsChronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which likely contributes to the increased susceptibility to infection in these patients.
Highlights
Monocytes are heterogeneous and highly plastic cells that play critical roles in host defence and tissue homeostasis
Peripheral blood monocyte surface marker (CD14, CD16, CD163, colony stimulating factor receptor (CSF1R), CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, major histocompatibility complex class II surface receptor (HLA-DR), CD62L, sialic acid binding Ig-like lectin (SIGLEC)-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated tumour necrosis factor (TNF) production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) and healthy controls (n = 11) by flow cytometry
Monocyte phenotypic signatures differed between NAFLD and chronic hepatitis C (HCV) patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV
Summary
Monocytes are heterogeneous and highly plastic cells that play critical roles in host defence and tissue homeostasis. Experimental models demonstrate that peripheral blood monocytes continuously traffic to (and probably from [1]) the healthy liver, but are recruited in increased numbers in the setting of liver injury, driving liver inflammation and fibrogenesis [2,3,4,5]. We and others have previously reported elevated numbers of liver monocytes/macrophages from the early stages of chronic liver disease (CLD) in patients with chronic hepatitis C (HCV) and non-alcoholic fatty liver disease (NAFLD)[6,7,8], in the absence of evidence of local proliferation, supporting a role for infiltrating monocyte-derived macrophages in human disease progression. CD16+ monocytes, which preferentially express the chemokine (C-X3-C motif) receptor (CX3CR), were traditionally designated pro-inflammatory, recent evidence supports a prominent role for the CD14highCD16+ ‘intermediate’ subset in inflammation, and angiogenic and surveillance functions for the CD14+/CD16+ ‘non-classical’ subset [9, 10]. Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence.
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