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

Kathleen E. Stevens, Chloe L. Thio, William O. Osburn

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)317-325
Number of pages9
JournalImmunology and Cell Biology
Volume97
Issue number3
DOIs
StatePublished - Mar 2019

Keywords

  • CXCR3
  • IL1b
  • IP-10
  • NK cells
  • proinflammatory monocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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