CCR5 deficiency enhances hepatic innate immune cell recruitment and inflammation in a murine model of acute hepatitis B infection. Issue 3 (24th January 2019)

• Record Type: Journal Article
• Authors: Stevens, Kathleen E; Thio, Chloe L; Osburn, William O
• Is Part Of: Immunology and cell biology. Volume 97:Issue 3(2019)
• Page Start: 317
• Page End: 325
• Publication Date: 2019-01-24
• Subjects: CXCR3 -- IL1b -- IP‐10 -- NK cells -- proinflammatory monocytes; Immunology -- Periodicals; Cytology -- Periodicals; 616.079
• DOI: 10.1111/imcb.12221
• Languages: English
• ISSNs: 0818-9641

Abstract

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. Abstract : In humans, the CCR5∆32 mutation is associated with enhanced control of hepatitis B virus (HBV). To elucidate the role of CCR5 deficiency in HBV infection, an adenoviral‐based murine model of acute HBV was established. At day 3 postinfection, CCR5 ‐deficient mice had enhanced intrahepatic CD11b + NK cells, which had potential to both degranulate and produce IFNg. CCR5 deficiency was associated with enhanced plasma levels of CXCL10, rather than CCR5 ligands, as observed in autoimmune hepatitis models. This suggests early recruitment of NK cells along the CXCR3 axis may be unique to HBV and increased in the absence of CCR5 signaling. By day 14, CCR5 ‐deficient mice had an enhanced intrahepatic proinflammatory monocyte population, and significantly increased serum alanine aminotransferase. Together, these findings suggest CCR5 ‐deficiency results in greater innate inflammatory infiltrates in the liver during acute HBV.