Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation

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.

Macrophage‐Specific Hypoxia‐Inducible Factor‐1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis

“…Our results demonstrate an increase in mouse hepatic macrophages after PA treatment in vitro and ex vivo . However, p62 levels were not modulated in human peripheral blood monocytes of patients with NASH, probably due to phenotypic differences observed in this cell, such as the increase in nonclassical phenotypes that have been related with NAFLD progression . Interpreting changes in p62 levels is complex because changes can be cell type– and context‐specific.…”

“…However, p62 levels were not modulated in human peripheral blood monocytes of patients with NASH, probably due to phenotypic differences observed in this cell, such as the increase in nonclassical phenotypes that have been related with NAFLD progression. (39,40) Interpreting changes in p62 levels is complex because changes can be cell type-and context-specific. Increased p62 levels may result from transcriptional upregulation observed under certain conditions or indicate the possible inhibition of autophagosome degradation.…”

Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials

“…Activation of these receptors induces migration of macrophages into the liver. 36 – 38 Cenicriviroc (CVC) is a CCR2/5 antagonist in phase 2 and phase 3 trials (NCT02217475 and NCT03028740).…”

Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus

“…However, CHC and NAFLD differentially affected the circulating monocyte phenotype, suggesting that unique injury-induced signals may contribute to the intrahepatic monocyte recruitment and the systemic activation state. Moreover, it was also shown that monocyte function was similarly impaired in patients with both CHC and NAFLD, particularly in advanced disease [ 28 ]. Thus, the manner of fibrosis progression resulting from inflammation could be different between NASH and CHC.…”