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

Abstract

Edited by Jeffrey PessinFibrosis, 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-␤ (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 proapoptotic 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.

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

“…[34][35][36] The ER plays a crucial role in maintaining cellular homeostasis, regulating protein synthesis, Ca 2+ transportation and drug metabolism. 37) It is widely accepted that ER stress and the downstream UPR exert both protective and detrimental effects on the cell.…”

Dietary zerumbone, a sesquiterpene, ameliorates hepatotoxin‐mediated acute and chronic liver injury in mice

“…Because carbon tetrachloride (CCl 4 ) is well‐documented among various toxins, it is widely used as a hepatotoxin in experimental animal model of ALI. Based on extensive studies, the initial event in the liver given CCl 4 is the induction of reactive oxygen species (ROS) generation and endoplasmic reticulum stress in hepatocytes, consequently triggering hepatocellular apoptosis and necrosis (Iracheta‐Vellve et al, ; Sun et al, ). If apoptotic hepatocytes are not rapidly removed by phagocytic cells such as Kupffer cells, membranes of these hepatocytes will break down, leading to secondary necrosis (Silva, ).…”

“…These dying cells induced by CCl 4 can also release cellular components recognized by hepatic immune cells, resulting in activation of inflammatory responses. Therefore, CCl 4 can induce persistent liver injury resulting in hepatic inflammation and consequent liver fibrosis when liver is exposed to it chronically or repetitively (Iracheta‐Vellve et al, ).…”

TRIF as a Novel Modulator of Liver Inflammation and Fibrosis

“…Activated HSCs in the NASH model potentially can have a key role modulating CXCL1 and/or CCL3-mediated recruitment of inflammatory cells. Supporting this notion are the findings of Iracheta-Vellve et al 5 showing that in the CCl4-mediated fibrosis model IRF3, the downstream target of TRIF, by its association to STING, is central to hepatocyte apoptosis and subsequent fibrosis. TRAM or TRIF deficiency in this model could not prevent fibrosis, consistent with the study in NASH.…”