title: ADAR1 Suppresses the Activation of Cytosolic RNA-Sensing Signaling Pathways to Protect the Liver from Ischemia/Reperfusion Injury.
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.
authors.affiliation: Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA.|Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA.
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
authors.forename: Junbin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
authors.forename: Jinxiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA.|Third Xiangya Hospital, Central South University, Changsha, China 410083.
authors.forename: Qingde
authors.initials: Q
authors.lastname: Wang
authors.affiliation: F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics* / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D016601:RNA-Binding Proteins; D012313:RNA; C000599465:ADAR1 protein, mouse; D000243:Adenosine Deaminase
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