Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes.
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 CCl4administration 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 CCl4administration 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 CCl4Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl4In 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.
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Arvin
A
Iracheta-Vellve
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Jan
J
Petrasek
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Benedek
B
Gyongyosi
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Abhishek
A
Satishchandran
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Patrick
P
Lowe
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Karen
K
Kodys
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Donna
D
Catalano
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Charles D
CD
Calenda
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Evelyn A
EA
Kurt-Jones
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Katherine A
KA
Fitzgerald
From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 gyongyi.szabo@umassmed.edu.
Gyongyi
G
Szabo
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005260:Female; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D000099197:STING Protein
D002251:Carbon Tetrachloride; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D053633:Receptor, Interferon alpha-beta; D051197:Toll-Like Receptor 4; C508032:Ifnar1 protein, mouse; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein
apoptosis; endoplasmic reticulum stress (ER stress); fibrosis; interferon regulatory factor (IRF); liver injury