ADAR1 Suppresses the Activation of Cytosolic RNA-Sensing Signaling Pathways to Protect the Liver from Ischemia/Reperfusion Injury.

Hui Wang,Jinxiang Zhang,Guoliang Wang,Liyong Zhang,Junbin Zhang,Qingde Wang,Timothy R Billiar

doi:10.1038/srep20248

Abstract

Excessive inflammation resulting from activation of the innate immune system significantly contributes to ischemia/reperfusion injury (IRI). Inflammatory reactions in both IRI and infections share the same signaling pathways evoked by danger/pathogen associated molecular pattern molecules. The cytosolic retinoid-inducible gene I(RIG-I)-like RNA receptor (RLR) RNA sensing pathway mediates type I IFN production during viral infection and the sensing of viral RNA is regulated by adenosine deaminase acting on RNA 1 (ADAR1). Using a model of liver IRI, we provide evidence that ADAR1 also regulates cytosolic RNA-sensing pathways in the setting of ischemic stress. Suppression of ADAR1 significantly enhanced inflammation and liver damage following IRI, which was accompanied by significant increases in type I IFN through cytosolic RNA-sensing pathways. In addition, knocking ADAR1 down in hepatocytes exaggerates inflammatory signaling to dsRNA or endotoxin and results in over production of type I IFN, which could be abolished by the interruption of RIG-I. Therefore, we identified a novel ADAR1-dependent protective contribution through which hepatocytes guard against aberrant cytosolic RLR-RNA-sensing pathway mediated inflammatory reaction in response to acute liver IR. ADAR1 protects against over activation of viral RNA-sensing pathways in non-infectious tissue stress.

Highlights

Ischemia/reperfusion (IR) is a major cause of liver damage during liver transplantation, hepatic resection, severe trauma, and hemorrhagic shock[1]
We adjusted adenosine deaminase acting on RNA 1 (ADAR1) expression in liver tissue or hepatocytes which were subjected to a variety of stress conditions and found that suppression of ADAR1 expression leads to increased RIG-I dependent type I IFN production, exaggerated inflammation, and greater organ damage following liver IR
ADAR1 protects hepatocytes from damage caused by hypoxia and reoxygenation

Summary

Results and Discussion

ADAR1 protects hepatocytes from damage caused by hypoxia and reoxygenation. . As expected cell damage induced by ADAR1 knockdown in response to H/R was prevented by BX795 (Fig. 5l) This result further confirmed that the RIG-I cytosolic RNA-sensing pathway was underlying the exaggerated type I IFN production in the IR-stressed liver when ADAR1 was downregulated. Suppression of ADAR1 significantly enhanced inflammation as well as liver damage following IR, which was accompanied by highly-expressed type I IFN in hepatocytes through cytosolic RLR-mediated RNA-sensing signaling pathways. Primary hepatocytes responded to other stressors such as endotoxin or dsRNA stimulation to activate this cytosolic RNA-sensing pathway, inducing type I IFN production and inflammatory reaction These results indicate that the cytosolic RNA-sensing signaling pathway through RLRs regulated by ADAR1 plays a crucial role in liver IRI and is potentially involved in other sterile tissue injuries. This novel signaling pathway may be a new drug target to prevent liver IRI or other stress-induced sterile organ injuries

Adenoviruses were prepared through a commercial service from

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