Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes

Arvin Iracheta-Vellve, Jan Petrasek, Benedek Gyongyosi, Abhishek Satishchandran, Patrick Lowe, Karen Kodys, Donna Catalano, Charles D. Calenda, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, G. Szabó

Research output: Contribution to journalArticle

27 Citations (Scopus)

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,TRAMor 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.

Original languageEnglish
Pages (from-to)26794-26805
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number52
DOIs
Publication statusPublished - Dec 23 2016

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Interferon Regulatory Factor-3
Endoplasmic Reticulum Stress
Liver Cirrhosis
Liver
Interferons
Hepatocytes
Genes
Wounds and Injuries
Fibrosis
Toll-Like Receptor 4
Apoptosis
Inflammation
Interleukins
Endoplasmic Reticulum
Liver Diseases
Chronic Disease
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. / 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.; Szabó, G.

In: Journal of Biological Chemistry, Vol. 291, No. 52, 23.12.2016, p. 26794-26805.

Research output: Contribution to journalArticle

Iracheta-Vellve, A, Petrasek, J, Gyongyosi, B, Satishchandran, A, Lowe, P, Kodys, K, Catalano, D, Calenda, CD, Kurt-Jones, EA, Fitzgerald, KA & Szabó, G 2016, 'Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes', Journal of Biological Chemistry, vol. 291, no. 52, pp. 26794-26805. https://doi.org/10.1074/jbc.M116.736991
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. ; Szabó, G. / Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 52. pp. 26794-26805.
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AU - Gyongyosi, Benedek

AU - Satishchandran, Abhishek

AU - Lowe, Patrick

AU - Kodys, Karen

AU - Catalano, Donna

AU - Calenda, Charles D.

AU - Kurt-Jones, Evelyn A.

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