NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

Taganov, Konstantin D.; Boldin, Mark; Chang, Kuang‐Jung; Baltimore, David

doi:10.1073/pnas.0605298103

Cited by 3,925 publications

(4,447 citation statements)

References 45 publications

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“…In particular, the miRNA-146a has been specifically associated with the regulation of TLR signaling (Cui et al, 2010;Quinn and O'Neill, 2011;Sheedy and O'Neill, 2008;Taganov et al, 2006). miRNA146a is expressed in human brain, and astrocytes have been shown to be key players in the regulation of this miRNA in response to inflammatory molecules, such as IL-1b Cui et al, 2010).…”

Section: Astrocytes As Source and Target Of Inflammatory Moleculesmentioning

confidence: 99%

Astrocyte immune responses in epilepsy

Aronica

Ravizza

Zurolo

et al. 2012

Glia

186

149

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Astrocytes, the major glial cell type of the central nervous system (CNS), are known to play a major role in the regulation of the immune/inflammatory response in several human CNS diseases. In epilepsy-associated pathologies, the presence of astrogliosis has stimulated extensive research focused on the role of reactive astrocytes in the pathophysiological processes that underlie the development of epilepsy. In brain tissue from patients with epilepsy, astrocytes undergo significant changes in their physiological properties, including the activation of inflammatory pathways. Accumulating experimental evidence suggests that proinflammatory molecules can alter glio-neuronal communications contributing to the generation of seizures and seizure-related neuronal damage. In particular, both in vitro and in vivo data point to the role of astrocytes as both major source and target of epileptogenic inflammatory signaling. In this context, understanding the astroglial inflammatory response occurring in epileptic brain tissue may provide new strategies for targeting astrocyte-mediated epileptogenesis. This article reviews current evidence regarding the role of astrocytes in the regulation of the innate immune responses in epilepsy. Both clinical observations in drug-resistant human epilepsies and experimental findings in clinically relevant models will be discussed and elaborated, highlighting specific inflammatory pathways (such as interleukin-1b/toll-like receptor 4) that could be potential targets for antiepileptic, disease-modifying therapeutic strategies. V

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Section: Astrocytes As Source and Target Of Inflammatory Moleculesmentioning

confidence: 99%

Astrocyte immune responses in epilepsy

Aronica

Ravizza

Zurolo

et al. 2012

Glia

186

149

View full text Add to dashboard Cite

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“…Recent studies have revealed that miR‐146 is primarily involved in the regulation of inflammation and other processes that function in the innate immune system (Sonkoly, Stahle & Pivarcsi, 2008). miR‐146a has been shown to be a circulating miRNA that is increased in synovial tissues and fibroblasts in rheumatoid arthritis (RA) patients as a particularly important negative regulator of nuclear factor‐κB (NF‐κB) signaling (Murata et al., 2010; Stanczyk et al., 2008; Taganov, Boldin, Chang & Baltimore, 2006). miR‐146a has also received much attention in the field of OA research.…”

Section: Introductionmentioning

confidence: 99%

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Guan

Yang

et al. 2018

Aging Cell

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SummaryPrimary osteoarthritis (OA) is associated with aging, while post‐traumatic OA (PTOA) is associated with mechanical injury and inflammation. It is not clear whether the two types of osteoarthritis share common mechanisms. We found that miR‐146a, a microRNA‐associated with inflammation, is activated by cyclic load in the physiological range but suppressed by mechanical overload in human articular chondrocytes. Furthermore, miR‐146a expression is decreased in the OA lesions of human articular cartilage. To understand the role of miR‐146a in osteoarthritis, we systemically characterized mice in which miR‐146a is either deficient in whole body or overexpressed in chondrogenic cells specifically. miR‐146a‐deficient mice develop early onset of OA characterized by cartilage degeneration, synovitis, and osteophytes. Conversely, miR‐146a chondrogenic overexpressing mice are resistant to aging‐associated OA. Loss of miR‐146a exacerbates articular cartilage degeneration during PTOA, while chondrogenic overexpression of miR‐146a inhibits PTOA. Thus, miR‐146a inhibits both OA and PTOA in mice, suggesting a common protective mechanism initiated by miR‐146a. miR‐146a suppresses IL‐1β of catabolic factors, and we provide evidence that miR‐146a directly inhibits Notch1 expression. Therefore, such inhibition of Notch1 may explain suppression of inflammatory mediators by miR‐146a. Chondrogenic overexpression of miR‐146a or intra‐articular administration of a Notch1 inhibitor alleviates IL‐1β‐induced catabolism and rescues joint degeneration in miR‐146a‐deficient mice, suggesting that miR‐146a is sufficient to protect OA pathogenesis by inhibiting Notch signaling in the joint. Thus, miR‐146a may be used to counter both aging‐associated OA and mechanical injury‐/inflammation‐induced PTOA.

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“…12 MiR-146a and miR-146b-5p are well studied miRs with multiple targets, whose gene and processing are rather well known. MIR146A (MIM# 610566) has two exons separated by a~16 kb intron 13,14 and is transcribed into a pri-miR of 2329 nt (GenBank accession number: EU147785.1); exon 2 contains the sequence of the pre-miR, which starts 53 nt from its 5ʹ-end. MIR146B (MIM# 610567) has only one exon and the transcription start site is located~700 nt upstream of the mature miR-146b-5p sequence, 14 but is not defined precisely, nor is identified the polyadenylation site.…”

Section: Introductionmentioning

confidence: 99%

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

et al. 2016

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Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

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NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

Cited by 3,925 publications

References 45 publications

Astrocyte immune responses in epilepsy

Astrocyte immune responses in epilepsy

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

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