ADAR1 deletion induces NFκB and interferon signaling dependent liver inflammation and fibrosis

Abstract

Adenosine deaminase acting on RNA (ADAR) 1 binds and edits double-stranded (ds) RNA secondary structures found mainly within untranslated regions of many transcripts. In the current research, our aim was to study the role of ADAR1 in liver homeostasis. As previous studies show a conserved immunoregulatory function for ADAR1 in mammalians, we focused on its role in preventing chronic hepatic inflammation and the associated activation of hepatic stellate cells to produce extracellular matrix and promote fibrosis. We show that hepatocytes specific ADAR1 knock out (KO) mice display massive liver damage with multifocal inflammation and fibrogenesis. The bioinformatics analysis of the microarray gene-expression datasets of ADAR1 KO livers reveled a type-I interferons signature and an enrichment for immune response genes compared to control littermate livers. Furthermore, we found that in vitro silencing of ADAR1 expression in HepG2 cells leads to enhanced transcription of NFκB target genes, foremost of the pro-inflammatory cytokines IL6 and IL8. We also discovered immune cell-independent paracrine signaling among ADAR1-depleted HepG2 cells and hepatic stellate cells, leading to the activation of the latter cell type to adopt a profibrogenic phenotype. This paracrine communication dependent mainly on the production and secretion of the cytokine IL6 induced by ADAR1 silencing in hepatocytes. Thus, our findings shed a new light on the vital regulatory role of ADAR1 in hepatic immune homeostasis, chiefly its inhibitory function on the crosstalk between the NFκB and type-I interferons signaling cascades, restraining the development of liver inflammation and fibrosis.

Both MAPK and STAT3 signal transduction pathways are necessary for IL-6-dependent hepatic stellate cells activation

“…In our earlier report, we demonstrated that IL-6 mediates the direct activation of HSCs in hepatocyte-specific ADAR1 knock-out mice [15]. The current study further characterized this role and demonstrated that both the MAPK and JAK/STAT3 signal transduction pathways are required for IL-6 activity.…”

Adenosine Deaminases Acting on RNA Downregulate the Expression of Constitutive Androstane Receptor in the Human Liver–Derived Cells by Attenuating Splicing

“…In addition, CAR is involved in the exacerbation of hepatic fibrosis in a mouse dietary model of nonalcoholic steatohepatitis (Yamazaki et al, 2007). A recent study reported that hepatocyte-specific ADAR1 knockout mice display massive liver damage with fibrogenesis, suggesting that ADAR1 restrains the development of hepatic fibrosis (Ben-Shoshan et al, 2017). Combined with the present findings that ADAR1 negatively regulates CAR expression, a possibility is surmised that ADAR1 has a role in protecting the liver from fibrosis by repressing CAR expression.…”

ADAR 1‐mediated RNA editing is required for thymic self‐tolerance and inhibition of autoimmunity

“…Nevertheless, we reveal for the first time that the presence of unedited endogenous dsRNAs triggered the aberrant activation of MDA5 in ADAR1‐deficient T cells, which was deleterious for their maturation. This is unique because ADAR1‐deficient cells usually exhibit widespread apoptosis with the enhanced expression of type I ISGs, which results in a severe reduction in the number of corresponding cells, such as hematopoietic stem cells, erythroid cells, B cell lineage cells, and hepatocytes . It is well known that treatment with poly(I:C), which mimics viral dsRNA and is commonly used as an MDA5 ligand, triggers pro‐apoptotic signaling in various cells .…”