Department of Medicine, Division of Gastroenterology; Department of Medicine, Division of Infectious Diseases and Immunology; UMass Metabolic Network
Biochemistry | Immunity | Molecular Biology
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 interferons (IFNs). In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the 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 carbontetrachloride (CCl4) administration to WT, IRF3-, TRAM-, TRIF-, and STING-deficient mice. We report that acute CCl4 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 CCl4. Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl4. 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 modulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.
apoptosis, endoplasmic reticulum stress (ER stress), fibrosis, interferon regulatory factor (IRF), liver injury
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Author's manuscript posted as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/Copyright_Permission.xhtml.
DOI of Published Version
J. Biol. Chem. jbc.M116.736991. doi:10.1074/jbc.M116.736991. Link to article on publisher's website.
The Journal of biological chemistry
Iracheta-Vellve, Arvin; Petrasek, Jan; Gyongyosi, Benedek; Satishchandran, Abhishek; Lowe, Patrick; Kodys, Karen; Catalano, Donna; Calenda, Charles D.; Kurt-Jones, Evelyn A.; Fitzgerald, Kate A.; and Szabo, Gyongyi, "Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via Stimulator of Interferon Genes." (2016). GSBS Student Publications. 1997.