Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion

Sato, Taku; Onai, Nobuyuki; Yoshihara, Hiroki; Arai, Fumio; Suda, Toshio; Ohteki, Toshiaki

doi:10.1038/nm.1973

Cited by 367 publications

(366 citation statements)

References 26 publications

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“…Here, IFN-β production acts as an autoregulatory mechanism controlling bone homeostasis [26]. Furthermore, basal levels of constitutive type I IFN have been shown to maintain and mobilize the HSC niche thereby regulating HSC homeostasis [27,28]. The regulation of constitutively induced type I IFN at the transcriptional level has mainly been studied in fibroblast cultures, in which it is clearly distinct from pathogen-induced IFN.…”

Section: Discussionmentioning

confidence: 99%

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Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

et al. 2014

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Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-α (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-α. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-α production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-α induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context. Keywords:CpG-A r CpG-B r pDC r TLR9 r Type I IFN Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe recognition of invading pathogens and the initiation of an appropriate immune response are key functions of the innate immune system. TLRs are a family of PRRs that sense conserved microbial signatures, also known as PAMPs [1,2]. Among these, TLR9 detects unmethylated CpG-motifs, which are present in viral Correspondence: Prof. Veit Hornung e-mail: veit.hornung@uni-bonn.de and bacterial DNA, whereas TLR7 senses uridine-rich RNA. To prevent recognition of endogenous nucleic acids, both TLR7 and TLR9 are confined to endosomal compartments that are usually devoid of nucleic acids. While both TLR7 and TLR9 are broadly expressed in innate immune cells of the murine system, both TLR7 and TLR9 show a far more restricted expression pattern within the human system, with TLR9 expression restricted to B cells and pDCs. * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 808Sarah Kim et al. Eur. J. Immunol. 2014. 44: 807-818 TLR9 traffics from the endoplasmic reticulum through the Golgi apparatus to acidic endosomal compartments, where it is proteolytically cleaved to achieve its signaling-competent state. Following ligand engagement, TLR9 initiates a signaling cascade, which is dependent on MyD88. In pDCs, MyD88 triggers a signaling complex consisting of IRAK1/4, TRAF3, and IKKα that leads to phosphorylation and nuclear translocation of interferon regulatory factor 7 (IRF7) and transcription of type I IFN genes. At the same time, TLR9 engagement activates NF-κB and subsequent proinflammatory gene expression [3]. For TLR9, di...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

et al. 2014

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“…In contrast, IFN-α/β receptor inactivation in mice showed minor change in the progenitor cell number [64]. Recently, a positive effect of IFN signaling on HSCs was reported [68,69]. The injection of IFN-α into mice stimulated quiescent LT-HSCs to enter the cell cycle, making them susceptible to 5-FU.…”

Section: Extracellular Signals Regulating Hscsmentioning

confidence: 99%

“…When IFN-α receptor was deleted in IRF2-deficient mice, a recovery of HSC reconstitution capacity was observed in Irf2-deficient HSCs. IFN-α can be considered a new player in the regulation of HSCs [69,71]. In addition to molecules that maintain the G0 state or support self-renewal in HSCs, molecules are desired that drive HSCs into the cell cycle or revert HSCs back to the G0 state IFN-γ was also found to stimulate quiescent HSCs in vivo [72].…”

Section: Extracellular Signals Regulating Hscsmentioning

confidence: 99%

Mechanisms of self-renewal in hematopoietic stem cells

Wang

Ema

2015

Int J Hematol

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“…Mice deficient for IRF2 show a substantial decrease of hematopoietic stem cells (HSCs) and a significant increase of immature progenitor cells. 35 Being essential for the preservation of the HSC pool, IRF2 normally suppresses IFN signaling in wild-type HSCs, thereby maintaining HSCs mostly in a quiescent state. In accordance, IFN-α stimulates the proliferation and turnover of dormant HSCs in vivo, and the cycling HSCs then become sensitive to antiproliferative chemotherapeutic agents, which are not effective for dormant HSCs.…”

Section: Ccnd1mentioning

confidence: 99%

Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia

Russ¹,

Sander²,

Lück³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMicroRNAs are regulators of gene expression, which act mainly by decreasing mRNA levels of their multiple targets. Deregulated microRNA expression has been shown for acute myeloid leukemia, a disease also characterized by altered gene expression associated with distinct genomic aberrations such as nucleophosmin (NPM1) mutations. To shed further light on the role of deregulated microRNA and gene expression in cytogenetically normal acute myeloid leukemia with NPM1 mutation we performed an integrative analysis of microRNA and mRNA expression data sets. Design and MethodsBoth microRNA and gene expression profiles were investigated in samples from a cohort of adult cytogenetically normal acute myeloid leukemia patients (n=43; median age 46 years, range 23-60 years) with known NPM1 mutation status (n=23 mutated, n=20 wild-type) and the data were integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative reverse transcriptase polymerase chain reaction, western blotting and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays. ResultsOur integrative approach of analyzing both microRNA-and gene expression profiles in parallel resulted in a refined list of putative target genes affected by NPM1 mutation-associated microRNA deregulation. Of 177 putative microRNA -target mRNA interactions we identified and validated 77 novel candidates with known or potential involvement in leukemogenesis, such as IRF2-miR-20a, . Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs, such as miR-29a and miR-30c, might contribute to sensitivity to cytarabine, which is observed in NPM1 mutated acute myeloid leukemia. ConclusionsOverall, our observations highlight that integrative data analysis approaches can improve insights into leukemia biology, and lead to the identification of novel microRNA -target gene interactions of potential relevance for acute myeloid leukemia treatment.Key words: microRNA, miRNA, gene expression profiling, GEP, acute myeloid leukemia, AML, NPM1 mutation.Citation: Russ AC, Sander S, Lück SC, Lang KM, Bauer M, Rücker FG, Kestler HA, Schlenk RF, Döhner H, Holzmann K, Döhner K, and Bullinger L. Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA -target gene interactions in acute myeloid leukemia.

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Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion

Cited by 367 publications

References 26 publications

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

Mechanisms of self-renewal in hematopoietic stem cells

Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia

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