ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes

Wang, Guoliang; Wang, Hui; Singh, Sucha; Zhou, Pei; Yang, Shiyu; Wang, Yujuan; Zhu, Zhaowei; Zhang, Jinxiang; Chen, Alex; Billiar, Timothy R.; Monga, Satdarshan P.; Wang, Q. Daniel

doi:10.1016/j.ajpath.2015.08.002

Cited by 43 publications

(34 citation statements)

References 75 publications

(51 reference statements)

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“…During the preparation of this manuscript, Wang et al 35 reported their findings in a similar model of hepatocyte specific ADAR1 KO. In agreement with our observations, they also show that Adar deletion in hepatocyte caused significant liver injury and alterations in synthetic liver functions coupled with increased mortality and severe growth defects of mutant mice.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 96%

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

et al. 2016

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“…Adenosine deaminase acting on RNA 1 (ADAR1) is a RNA-binding/editing protein and plays an anti-inflammatory role by suppressing cytosolic innate immune sensing of dsRNA by RLRs. ADAR1 has been found to be essential in maintaining liver homeostasis by preventing hepatocyte inflammation and cell death 36 . In liver IRI, ADAR1 expression was induced.…”

Section: Innate Immune Activationmentioning

confidence: 99%

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

et al. 2016

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Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory, but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver IRI involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver IRI in patients.

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“…IFN-I also has important effects on lethality in diverse models of sepsis or endotoxic shock (8). In addition, numerous studies have suggested that excessive IFN-I signaling could be involved in impairing normal organismal homoeostasis, including the maintenance of both fetal and adult hematopoietic stem cells (9), intestinal homoeostasis (10), and liver morphological and functional integrity (11).…”

mentioning

confidence: 99%

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

Qian

Zuo

et al. 2016

Journal of Biological Chemistry

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Edited by George DeMartinoAdenosine deaminase acting on RNA 1 (ADAR1) catalyzes RNA editing of cellular and viral RNAs. Besides RNA editing, ADAR1 has recently been shown to play important roles in maintaining the body balance, including tissue homoeostasis, organ development, and autoimmune regulations, by inhibiting both IFN production and subsequent IFN-activated pathways. Accordingly, the question was raised how IFN signaling induced by viral infections overcomes the inhibitory effect of constitutively expressed ADAR1 (ADAR1-P110) to execute efficient antiviral activity. Here we unexpectedly found that IFN signaling promoted Lys 48 -linked ubiquitination and degradation of ADAR1-P110. Furthermore, we identified the E3 ligase ␤ transducin repeat-containing protein responsible for IFN-mediated ADAR1-P110 down-regulation. IFN signaling promoted the interaction between ␤ transducin repeat-containing protein and ADAR1-P110 as well as protein turnover of ADAR1-P110. Moreover, we found that both lysine 574 and 576 are essential for ADAR1-P110 ubiquitination. Critically, we demonstrated that down-regulation of ADAR1-P110 is required for IFN signaling to execute efficient antiviral activity during viral infections. These findings renew the understanding of the mechanisms by which IFN signaling acts to achieve antiviral functions and may provide potential targets for IFN-based antiviral therapy.

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ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes

Cited by 43 publications

References 75 publications

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

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

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

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