Impaired Monocyte-Macrophage Functions and Defective Toll-Like Receptor Signaling in Hepatitis E Virus-Infected Pregnant Women With Acute Liver Failure

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Abstract

Acute viral hepatitis resulting due to hepatitis E viral infection (AVH-E) is often serious in pregnancy and could result in acute liver failure (ALF). The role of monocytes and macrophages (mono-macs) in the pathogenesis of AVH-E and development of ALF-E in pregnancy is unclear. We investigated the functions of mono-macs in pregnant (P), AVH-E (n = 44), ALF-E (n = 12), healthy controls (HC; n = 20) and compared with nonpregnant (NP) AVH-E (n = 10), ALF-E (n = 5), and HC (n = 10). We also recruited non-hepatitis E virus-related pregnant (P), ALF-NE (n = 5) and non-pregnant (NP), ALF-NE (n = 12) patients with ALF. Mono-macs, dendritic cell (DC) phenotypes, and Toll-like receptor (TLR) expressions were studied by flow cytometry and reverse-transcriptase polymerase chain reaction. Mono-macs functionality was determined by analyzing their phagocytic activity and reactive oxygen species (ROS) generation by using flow cytometry. Frequency of mono-macs and DCs was increased during HEV infection compared to HC (P< 0.001). Macrophages were increased (P< 0.002) in ALF-E(P) compared to ALF-NE(P). The macrophage phagocytic activity andEscherichia coli-induced ROS production was significantly impaired in ALF-E(P) compared to AVH-E(P) (P< 0.001), ALF-E(NP), and ALF-NE(P) patients (P< 0.02). TLR3 and TLR9 expression and downstream MYD88 signalling molecules IRF3 and IRF7 were significantly down-regulated in ALF-E(P) (P< 0.00) compared to AVH-E(P) and ALF-NE(P).

Conclusion:

Functionality of mono-macs is impaired in pregnant ALF-E patients compared to AVH-E(P). Reduced TLR3 and TLR7 expression and TLR downstream-signaling molecules in pregnant ALF-E patients suggests inadequate triggers for the innate immune responses contributing to development and severity of ALF-E. Studies using TLR agonists to activate mono-macs may be of use andin vitrostudies should be undertaken using patient samples.(Hepatology 2015;62:1683–1696)

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