title: 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.
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.|d Sackler Faculty of Medicine , Tel Aviv University , Israel.
authors.forename: Shirley Oren
authors.initials: SO
authors.lastname: Ben-Shoshan
authors.affiliation: b Liver Research Laboratory , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.|d Sackler Faculty of Medicine , Tel Aviv University , Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Kagan
authors.affiliation: b Liver Research Laboratory , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Sultan
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Barabash
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Dor
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.|e The Mina and Everard Goodman Faculty of Life Sciences , Bar Ilan University , Ramat Gan , Israel.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.affiliation: f Department of Veterinary Resources , Weizmann Institute of Science , Rehovot , Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Harmelin
authors.affiliation: c Department of Pathology , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Marcu-Malina
authors.affiliation: b Liver Research Laboratory , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.|d Sackler Faculty of Medicine , Tel Aviv University , Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Ben-Ari
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.|e The Mina and Everard Goodman Faculty of Life Sciences , Bar Ilan University , Ramat Gan , Israel.
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.|d Sackler Faculty of Medicine , Tel Aviv University , Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: a Sheba Cancer Research Center , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.|d Sackler Faculty of Medicine , Tel Aviv University , Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goldstein
authors.affiliation: b Liver Research Laboratory , Chaim Sheba Academic Medical Center, Tel Hashomer , Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Safran
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics*; D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism; D006505:Hepatitis / Q000235:genetics* / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D019899:Paracrine Communication / Q000276:immunology; D012330:RNA, Double-Stranded / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508606:CXCL8 protein, human; C508600:IL6 protein, human; D007370:Interferon Type I; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012330:RNA, Double-Stranded; C000599465:ADAR1 protein, mouse; D000243:Adenosine Deaminase
keywords: ADAR1; Interleukin 6 (IL6); RNA editing; epitranscriptome; fibrosis; hepatic stellate cells; inflammation; interferon; liver; NFκB pathway