Abstract
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 CCl4 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 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 regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.
Highlights
Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases
Interferon regulatory factor 3 (IRF3) Deficiency Attenuates Chronic CCl4-mediated Liver Injury and Fibrosis—Repetitive episodes of liver injury, such as those induced by administration of CCl4, result in the development of liver fibrosis, which is a hallmark of advanced and often irreversible liver disease in humans
We demonstrated earlier that stimulator of interferon genes (STING) and IRF3 mediate the pathogenesis in alcoholic liver disease, a role independent of microbial components [8]
Summary
Driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. 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. IRF3 associated with the pro-apoptotic adaptor Bax and triggered apoptosis in murine embryonic fibroblasts and murine hepatocytes (6 – 8) It is not known whether other key signal transduction events in hepatocytes are required for the pathogenesis of fibrosis. Using two models of CCl4-induced liver injury, we investigated the complex multicellular events associated with fibrosis in a chronic model, as well as the tightly controlled signal transduction events associated with early disruption of homeostasis and cell death in the acute model. Activated IRF3 associates with the pro-apoptotic adaptor Bax and induces hepatocyte death. Our data demonstrate that hepatocyte death is indispensable in liver fibrosis and that the pathogenic role of IRF3 in liver fibrosis is mediated via its pro-apoptotic effect in hepatocytes
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