CCR5 deficiency enhances hepatic innate immune cell recruitment and inflammation in a murine model of acute hepatitis B infection.

Abstract

Human genetic studies demonstrate a link between the 32-bp deletion that produces a nonfunctional CCR5 receptor and enhanced recovery from acute hepatitis B virus (HBV) infection. To investigate the role of CCR5 in immune responses to acute HBV, we intravenously infected Ccr5+/+ (WT) and Ccr5-/- (KO) mice with a replication-incompetent adenovirus containing the overlapping HBV1.3 construct (AdHBV), or vector control. At day 3 following AdHBV infection, analysis of intrahepatic leukocytes (IHL) showed KO mice had increased CD11b+ NK cells compared to WT (18.2% versus 7.6% of live IHL, P < 0.01). These CD11b+ NK cells were nonresident (CD49a- ) and had capacity to degranulate and produce IFN-γ following stimulation. At day 3, plasma CXCL10 was significantly increased in KO, but not WT, mice receiving AdHBV as compared to vector control, while CXCR3 expression on hepatic CD11b+ NK cells in AdHBV-treated KO mice was significantly lower than that in uninfected mice, suggesting these NK cells are recruited along the CXCL10-CXCR3 axis. At days 7 and 14, no differences between genotypes were observed in number, or HBV-specific function, of intrahepatic CD8+ T cells. Instead, at day 14, KO mice had increased intrahepatic proinflammatory monocytes compared to WT mice (17.56% versus 6.57% of live IHL, P = 0.014), corresponding with an increase in plasma alanine aminotransferase and intrahepatic IL-1β observed in KO mice. Taken together, these findings demonstrate that loss of CCR5 signaling drives a more robust inflammatory liver microenvironment early in acute HBV infection via enrichment of hepatic innate immune cells.

• Authors: Kathleen E Stevens, Chloe L Thio, William O Osburn
• Journal: Immunology and cell biology (Immunol Cell Biol) Vol. 97 Issue 3 Pg. 317-325 (03 2019) ISSN: 1440-1711 [Electronic] United States
• PMID: 30536991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Australasian Society for Immunology Inc.

Chemical References

• Biomarkers
• Receptors, CCR5

Topics

• Animals
• Biomarkers
• Cell Degranulation (immunology)
• Chemotaxis, Leukocyte (genetics, immunology)
• Disease Models, Animal
• Disease Susceptibility
• Gene Expression
• Hepatitis B (etiology, metabolism, pathology)
• Hepatitis B virus
• Humans
• Immunity, Innate (genetics)
• Immunophenotyping
• Killer Cells, Natural (immunology, metabolism)
• Leukocytes (immunology, metabolism)
• Male
• Mice
• Mice, Knockout
• Receptors, CCR5 (deficiency)
• Spleen (cytology, immunology, metabolism)
• T-Lymphocyte Subsets (immunology, metabolism)