ADAR1 attenuates allogeneic graft rejection by suppressing miR‐21 biogenesis in macrophages and promoting M2 polarization

Liu, Jun-Jie; Xie, Jiangang; Liu, Shanshou; Li, Xiao; Zhang, Dongliang; Wang, Xianqi; Jiang, Jie; Hu, Wei; Zhang, Yuan; Jin, Boquan; Zhuang, Ran; Yin, Wen

doi:10.1096/fj.201701449r

Cited by 29 publications

(25 citation statements)

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“…LPS was used to stimulate RAW 264.7 macrophages. The expression of ADAR1 was first increased and then decreased after day 2; this agrees with our previous observation that ADAR1 was increased within 24 h after LPS activation [10]. SOCS3 is a key molecule involved in the negative regulation of cytokines that signal through the JAK/STAT3 pathway.…”

Section: Adar1 Regulates Expression Of Il-6 In Macrophages Via Socs3supporting

confidence: 91%

“…Our previous studies showed that overexpression of ADAR1 reduces the mortality of mice with infections [10]. We found that the levels of IL-6, TNF-α, IL-1β, and MCP-1 were significantly increased at 24 h after sepsis.…”

Section: Discussionmentioning

confidence: 73%

“…However, the biological significance of these changes is not completely understood. Our previous studies demonstrated that ADAR1 suppresses miR-21 maturation, upregulates the expression of forkhead box protein O1 (Foxo1), promotes interleukin-(IL-) 10 expression, modulates macrophage M2 polarization, and alleviates allogeneic graft rejection [10]. In addition, overexpression of ADAR1 can reduce the mortality of mice with infection, and suppression of ADAR1 in mice with sepsis significantly enhanced inflammation and intestinal damage, whereas overexpression of ADAR1 significantly reduced damage and inflammation, thus improving the survival of mice with sepsis [11].…”

Section: Introductionmentioning

confidence: 99%

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ADAR1 Alleviates Inflammation in a Murine Sepsis Model via the ADAR1-miR-30a-SOCS3 Axis

Zhou

Liu

Zhao

et al. 2020

Mediators of Inflammation

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Adenosine deaminase acting on double-stranded RNA 1 (ADAR1) mediates adenosine-to-inosine (A-to-I) RNA editing events. ADAR1 is highly expressed in “septic” macrophages and in small intestinal tissues of mice with sepsis. Overexpression of ADAR1 suppresses inflammation and intestinal damage. However, the specific underlying mechanism is unclear. This study was conducted to explore how microRNA (miRNA) regulates the anti-inflammatory mechanism of macrophages following ADAR1 upregulation. A murine sepsis model was established by cecal ligation and puncture (CLP). Mice were randomly assigned to sham, CLP, and CLP+ADAR1 groups. Hematoxylin and eosin (HE) staining and fluorescence isothiocyanate-dextran were used to evaluate intestinal injury and permeability. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and Luminex assays were performed to detect changes in the expression of inflammatory cytokines. Adenoviruses were used to express ADAR1 in RAW 264.7 cells. Ribonucleoprotein immunoprecipitation analysis was conducted to detect the binding of ADAR1 and miRNAs. A dual-luciferase reporter assay was used to detect the binding of miRNAs and regulatory factors. We observed that ADAR1 significantly increased the expression of suppressor of cytokine signaling 3 (SOCS3) in macrophages and reduced the expression of interleukin-6 in macrophages and the serum, thereby reducing intestinal permeability and mucosal injury in mice with sepsis. The RNA-ribonucleoprotein immunoprecipitation binding assay and qRT-PCR demonstrated a direct interaction between ADAR1 and pri-miR-30a. The luciferase assay demonstrated that SOCS3 was significantly inhibited by miR-30a-5p, the mature product of miR-30a. Thus, ADAR1 exerts a protective effect against sepsis by reducing inflammation and organ damage via the ADAR1-miR-30a-SOCS3 axis.

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Section: Adar1 Regulates Expression Of Il-6 In Macrophages Via Socs3supporting

confidence: 91%

Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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ADAR1 Alleviates Inflammation in a Murine Sepsis Model via the ADAR1-miR-30a-SOCS3 Axis

Zhou

Liu

Zhao

et al. 2020

Mediators of Inflammation

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“…This opposite observation may be caused by the immortalization and transformation of the cell line. miR-21 targets phosphatase and tensin homolog (PTEN), which inhibits the phosphoinositide 3-kinase (PI3K)/Akt pathway [37]. As one of the most extensively studied signaling pathways, the PI3K/Akt pathway is involved in almost every aspect of macrophage activation [38,39].…”

Section: Discussionmentioning

confidence: 99%

Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb

et al. 2020

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Background: M2 macrophages and exosomes from adipose-derived stem cells (ASCs) are both reported to promote angiogenesis. However, the possible synergistic effects between exogenous exosomes and endogenous M2 macrophages are poorly understood.Methods: Exosomes were isolated from conditioned medium of normoxic and hypoxic ASCs using the combined techniques of ultrafiltration and size-exclusion chromatography and were identified with nanoparticle tracking analysis and immunoblotting for exosomal markers. Macrophages were collected from the mouse peritoneal cavity. M1 and M2 macrophages were detected by immunoblotting for the intracellular markers inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) and by flow cytometry for the surface markers F4/80, CD86, and CD206. Murine models of Matrigel plug and hindlimb ischemia were employed as in vivo angiogenic assays.(Continued on next page) Results: When M1 macrophages were treated with exosomes from normoxic ASCs (Nor/Exo), and particularly from hypoxic ASCs (Hyp/Exo), the expression of the M1 marker iNOS decreased, and the M2 marker Arg-1 increased in a time-and dosedependent manner. Additionally, a decrease in the M1 surface marker CD86 and an increase in the M2 surface marker CD206 were observed, which suggested that M1 macrophages were polarized to an M2-like phenotype. Conditioned medium from these M2-like macrophages presented lower levels of proinflammatory cytokines and higher levels of proangiogenic factors and promoted endothelial cell proliferation, migration, and tube formation. Furthermore, M2 polarization and angiogenesis were induced upon the administration of exosomes in mouse Matrigel plug and hindlimb ischemia (HLI) models. Interestingly, these exosomal effects were attenuated by using a colony stimulating factor 1 receptor (CSF-1R) inhibitor, BLZ945, in vitro and in vivo. Downregulation of microRNA-21 (miR-21) in hypoxic ASCs reduced the exosomal effects on M2 polarization, Akt phosphorylation, and CSF-1 secretion. A similar reduction in exosomal activity was also observed when exosomes were administered along with BLZ945.Conclusion: Our findings provide evidence that exosomes from ASCs polarize macrophages toward an M2like phenotype, which further enhances the exosomal proangiogenic effects. Exosomal delivery of miR-21 and positive feedback of secreted CSF-1 may be involved in macrophage polarization.

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“…ADAR1 may regulate IFN pathway components by recoding editing [39][40][41]; in cancer models, site-specific RNA editing at some sites increased following stimulation with IFN [40]. The idea that ISG transcripts are particularly targeted by ADARs is notable in the context of the proposed central role of ADARs in meditating IFN response.…”

Section: Other Adar1 Effects On Innate Immunitymentioning

confidence: 99%

ADAR RNA Modifications, the Epitranscriptome and Innate Immunity

Quin

Sedmik

Vukić

et al. 2021

Trends in Biochemical Sciences

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Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosineto-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I-like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer. The Epitranscriptome, ADARs, and InosinesModified bases act as marks of self-RNA to reduce innate immune responses to endogenous cellular RNA. Over 170 different types of enzymatic RNA modifications are known to occur in stable RNAs, such as tRNAs and rRNAs, where many contribute to their high stabilities and optimise the activities of these RNAs [1]. Different types of base modifications have also been found in eukaryotic mRNAs, where they are called epitranscriptomic (see Glossary) modifications [2]. Base modifications that have been detected in mRNA include adenosine to inosine (A-to-I) deamination and cytosine to uracil (C-to-U) deamination, N 6 -methyladenosine (m 6 A), N 1 -methyladenosine (m 1 A), 5-methylcytosine (5mC), and pseudouridine (ψ), as well as ribose 2′O-methyl [1]. Many of these modifications affect innate immune responses to RNA [3-6], and understanding these effects has been critical for development of mRNA therapeutics and vaccines [7].We focus here on A-to-I deamination, which was one of the first RNA base modifications identified; it is abundant in tRNAs and plays a key role in tRNA wobble decoding. It was also one of the first epitranscriptomic mRNA modifications identified, because it is readily detected by RNA sequencing (RNA-seq). A-to-I RNA modification/editing found in mRNAs is catalysed by adenosine deaminases acting on RNAs (ADARs). In mammals, there are three ADAR family members: ADAR1 and ADAR2 deaminate double-stranded (ds)RNA, whereas ADAR3 is enzymatically inactive (for review, see [8]). This review focuses primarily on ADAR1, summarising the evidence for its role in innate immunity (Figure 1) and how this role of ADARs is evolutionarily conserved. We also aim to clarify how and when A-to-I conversion acts as an epitranscriptomic RNA modification versus the rarer cases where it acts as an RNA editing event. This RNA modification role of the ADARs has been, and will continue to be, a trailblazer for understanding epitranscriptomic roles of many types of RNA modifications. Finally, we also summarise human diseases and SNPs associated with ADAR1 and the roles of ADAR1 in tumour immunity. ADAR1, the Inosinome, and Effects on Three Levels ADAR1The three ADARs are composed of two or more dsRNA-binding domains (dsRBDs) followed ...

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ADAR1 attenuates allogeneic graft rejection by suppressing miR‐21 biogenesis in macrophages and promoting M2 polarization

Cited by 29 publications

References 50 publications

ADAR1 Alleviates Inflammation in a Murine Sepsis Model via the ADAR1-miR-30a-SOCS3 Axis

ADAR1 Alleviates Inflammation in a Murine Sepsis Model via the ADAR1-miR-30a-SOCS3 Axis

Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb

ADAR RNA Modifications, the Epitranscriptome and Innate Immunity

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