title: Central role of the TIR-domain-containing adaptor-inducing interferon-β (TRIF) adaptor protein in murine sterile liver injury.
abstract: Multiple pathways drive the sterile injury response in the liver; however, it is unclear how the type of cells injured or the mechanism of injury activates these pathways. Here, we use a model of selective hepatocyte death to investigate sterile liver injury. In this model, the TIR-domain-containing adaptor-inducing interferon-β (TRIF) was a central mediator of the resulting intrahepatic inflammatory response that was independent of both upstream Toll-like receptor (TLR) 4 signaling and downstream type I interferon (IFN) signaling. TRIF was required for induction of interleukin (IL)-10, IL-6, and IL-1β cytokines. Conversely, although induction of C-C motif chemokine ligand (CCL) 2 and C-X-C motif chemokine ligand (CXCL) 1 chemokines and up-regulation of chemokine (Ccl2, Ccl7, Cxcl1, Cxcl2, and Cxcl10) and cell-adhesion (intracellular adhesion molecule 1 and vascular cell adhesion molecule 1) genes involved in myeloid cell recruitment was reduced in a majority of TRIF-/-mice, a subset of TRIF-/-mice showed breakthrough inflammation and the ability to induce these genes and proteins, indicating that redundant pathways exist to respond to hepatocyte death. Furthermore, we found that hepatocytes themselves were the main responders to hepatocyte death, increasing transcription of genes involved in myeloid cell recruitment more than either liver sinusoidal endothelial cells or Kupffer cells.
  
  
  
  Our studies define a TRIF-dependent, TLR4- and type I IFN-independent pathway of sterile liver injury in which hepatocytes are both the targets of damage and the principal responding cell type. (Hepatology 2017;65:1336-1351).
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA.|Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Brempelis
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Sebastian Y
authors.initials: SY
authors.lastname: Yuen
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schwarz
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Mohar
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Crispe
mesh_terms: D000208:Acute Disease; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D016899:Interferon-beta / Q000235:genetics*; D008099:Liver / Q000293:injuries*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D015854:Up-Regulation; D014947:Wounds and Injuries / Q000235:genetics / Q000503:physiopathology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016899:Interferon-beta; C476286:Ticam1 protein, mouse