title: Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstruction.
abstract: Both Kupffer cells and invariant natural killer T (iNKT) cells suppress neutrophil-dependent liver injury in a mouse model of biliary obstruction. We hypothesize that these roles are interdependent and require iNKT cell-Kupffer cell cross-activation. Female, wild-type and iNKT cell-deficient C57Bl/6 mice were injected with magnetic beads 3 days prior to bile duct ligation (BDL) in order to facilitate subsequent Kupffer cell isolation. On day three post-BDL, the animals were euthanized and the livers dissected. Necrosis was scored; Kupffer cells were isolated and cell surface marker expression (flow cytometry), mRNA expression (qtPCR), nitric oxide (NO (.) ) production (Griess reaction), and protein secretion (cytometric bead-array or ELISAs) were determined. To address the potential role of NO (.) in suppressing neutrophil accumulation, a group of WT mice received 1400W, a specific inducible nitric oxide synthase (iNOS) inhibitor, prior to BDL. To clarify the mechanisms underlying Kupffer cell-iNKT cell cross-activation, WT animals were administered anti-IFN-γ or anti-lymphocyte function-associated antigen (LFA)-1 antibody prior to BDL. Compared to their WT counterparts, Kupffer cells obtained from BDL iNKT cell-deficient mice expressed lower iNOS mRNA levels, produced less NO (.) , and secreted more neutrophil chemoattractants. Both iNOS inhibition and IFN-γ neutralization increased neutrophil accumulation in the livers of BDL WT mice. Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury.
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Duwaerts
authors.forename: Eric P
authors.initials: EP
authors.lastname: Sun
authors.forename: Chao-Wen
authors.initials: CW
authors.lastname: Cheng
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gregory
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000293:injuries* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D052247:Nitric Oxide Synthase Type II