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CCR5 deficiency enhances hepatic innate immune cell recruitment and inflammation in a murine model of acute hepatitis B infection
Author(s) -
Stevens Kathleen E,
Thio Chloe L,
Osburn William O
Publication year - 2019
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.12221
Subject(s) - innate immune system , inflammation , immunology , immune system , acute hepatitis , medicine , virology , hepatitis , biology
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.