Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Content Provider	Scilit
Author	Iracheta-Vellve, Arvin Petrasek, Jan Gyongyosi, Benedek Satishchandran, Abhishek Lowe, Patrick Kodys, Karen Catalano, Donna Calenda, Charles D. Kurt-Jones, Evelyn A. Fitzgerald, Katherine A. Szabo, Gyongyi
Copyright Year	2016
Description	Journal: Journal of Biological Chemistry Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic $CCl_{4}$ administration to WT and IRF3-, Toll/Interleukin-1R (TIR) domain-containing adapter-inducing interferon-β (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute $CCl_{4}$ administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of $CCl_{4}$. Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic $CCl_{4}$. In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the pro-apoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.
Related Links	http://www.jbc.org/content/291/52/26794.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207187/pdf http://www.jbc.org/article/S0021925820344318/pdf
Ending Page	26805
Page Count	12
Starting Page	26794
ISSN	00219258
e-ISSN	1083351X
DOI	10.1074/jbc.m116.736991
Journal	Journal of Biological Chemistry
Issue Number	52
Volume Number	291
Language	English
Publisher	Elsevier BV
Publisher Date	2016-12-01
Access Restriction	Open
Subject Keyword	Journal: Journal of Biological Chemistry Endoplasmic Reticulum Stress (er Stress) Interferon Regulatory Factor (irf) Liver Injury
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology