Central role of the TIR‐domain‐containing adaptor‐inducing interferon‐β (TRIF) adaptor protein in murine sterile liver injury

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 IFN signaling. TRIF was required for the induction of IL-10, IL-6, and IL-1β cytokines. Conversely, although the induction of CCL2 and CXCL1 chemokines and the up-regulation of chemokine (Ccl2, Ccl7, Cxcl1, Cxcl2, and Cxcl10) and cell-adhesion (Icam1 and Vcam1) 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 (LSECs) or Kupffer cells (KCs). Conclusion: 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. This article is protected by copyright. All rights reserved.