title: Roles of dendritic cells in murine hepatic warm and liver transplantation-induced cold ischemia/reperfusion injury.
abstract: Dendritic cells (DCs) induce and regulate both innate and adaptive immune responses; however, their in vivo functional importance in hepatic ischemia/reperfusion (IR) injury is perplexing. We hypothesized that liver-resident DC and locally recruited blood-borne DC might have distinctive roles in hepatic IR injury. We tested this hypothesis by using DC-deficient, fms-like tyrosine kinase 3 ligand (Flt3L) knockout (KO) mice in hepatic warm (70% partial clamping for 60 minutes) and cold IR injury (liver transplant [LTx] with 24-hour cold storage). Flt3L KO liver and lymphoid organs contained virtually no CD11c+ F4/80- DC. Hepatic warm IR injury was significantly lower in Flt3L KO than in wildtype (WT) mice with lower alanine aminotransferase (ALT) levels, reduced hepatic necrosis, and lower neutrophil infiltration. Hepatic messenger RNA (mRNA) and protein levels for inflammatory cytokines (tumor necrosis factor alpha [TNFα], interleukin [IL]-6) and chemokines (CCL2, CXCL2) were also significantly lower in Flt3L KO than in WT mice, indicating that lack of both liver-resident and blood-borne DC ameliorated hepatic warm IR injury. Adoptive transfer of splenic or hepatic WT DC into Flt3L KO or WT mice increased hepatic warm IR injury, suggesting injurious roles of DC infusion. When Flt3L KO liver was transplanted into WT mice, ALT levels were significantly higher than in WT to WT LTx, with enhanced hepatic necrosis and neutrophil infiltration, indicating a protective role of liver-resident DC.
  
  
  CONCLUSIONS
  Using both warm and cold hepatic IR models, this study suggests differential roles of liver-resident versus blood-borne DC, and points to the importance of the local microenvironment in determining DC function during hepatic IR injury.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zhang
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueki
authors.forename: Shoko
authors.initials: S
authors.lastname: Kimura
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshida
authors.forename: Antonino
authors.initials: A
authors.lastname: Castellaneta
authors.forename: Kikumi S
authors.initials: KS
authors.lastname: Ozaki
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.forename: Donna
authors.initials: D
authors.lastname: B Stolz
authors.forename: David A
authors.initials: DA
authors.lastname: Geller
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D050377:Cold Ischemia / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D007113:Immunity, Innate; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D016031:Liver Transplantation; D008221:Lymphoid Tissue / Q000473:pathology / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009336:Necrosis; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D052096:Warm Ischemia / Q000009:adverse effects*
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; C084881:flt3 ligand protein; D000410:Alanine Transaminase