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Sci Rep. 2016 Feb 1;6:20248. doi: 10.1038/srep20248.

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

Author information

1
Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
2
F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA.
3
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
4
Third Xiangya Hospital, Central South University, Changsha, China 410083.

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.

PMID:
26832817
PMCID:
PMC4735287
DOI:
10.1038/srep20248
[Indexed for MEDLINE]
Free PMC Article

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