IRF-7 triggers the interferon alarm

Raftopoulou, Myrto

doi:10.1038/ncb0505-459

Cited by 3 publications

(3 citation statements)

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“…Human pDCs mostly express TLRs, which recognize ssRNA (TLR7 and TLR8) or dsCpG‐rich DNA (TLR9) [15]. Recognition of viral nucleic acids by TLRs activates IRF‐7, which transcriptionally activates multiple IFN‐α genes [16,17]. A major difference between pDCs and other cell types is their capacity to constitutively produce relatively high concentrations of IRF‐7 [18].…”

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Promoters of type I interferon genes from Atlantic salmon contain two main regulatory regions

Bergan¹,

Steinsvik²,

Xu³

et al. 2006

The FEBS Journal

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The type I interferon (IFN) system plays a critical role in the innate immune defense against viruses in vertebrates. Virus-infected cells synthesize and secrete type I interferons (IFN-a ⁄ b), which circulate in the body and protect other cells from viral infection. The antiviral action is caused by binding of IFN-a ⁄ b to the type I IFN receptor resulting in activation of transcription of several hundred IFN-stimulated genes, some of which encode proteins that inhibit viral replication. The antiviral properties of at least three type I IFNinduced proteins are well established. These comprise dsRNA-activated protein kinase R (PKR), 2¢,5¢-oligoadenylate synthetase and Mx proteins [1].Although the structures of the IFN-a and IFN-b promoters from human and mouse have been long known, the mechanisms involved in viral induction of type I IFNs have only recently been uncovered [2,3]. Of great importance has been the discovery of IFN super-producing blood cells called plasmacytoid dendritic cells (pDCs) and the realization that the Keywords Atlantic salmon; interferon promoter; interferon regulatory factor; nuclear factor kappa B (NFjB); poly(I:C) Correspondence B. Robertsen,

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Promoters of type I interferon genes from Atlantic salmon contain two main regulatory regions

Bergan¹,

Steinsvik²,

Xu³

et al. 2006

The FEBS Journal

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“…IRF7 is the master transcriptional regulator of the IFN-I-dependent immune response. 27 , 40 The regulatory mechanism of IRF7 in activated microglia is unclear. Using targeted resequencing of 215 candidate genes involved in autoimmunity in Swedish cohorts, a rare regulatory variant rs200395694: G>T located in intron 4 of the MEF2D gene was identified to be associated with systemic lupus erythaematosus, a chronic inflammatory autoimmune disease with excessive production of IFN-Is and autoantibodies against nucleic acids as hallmarks.…”

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confidence: 99%

Regulation of IFN-Is by MEF2D Promotes Inflammatory Homeostasis in Microglia

Wang

et al. 2021

JIR

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Background Microglia play an essential role in the central nervous system immune response. The transcription factor myocyte enhancer factor-2 D (MEF2D) is known to participate in stress regulation in various cell types and is easily activated in microglia. MEF2D has been shown to transcriptionally regulate several cytokine genes in immune cells and directly regulates the inflammatory response, suggesting that MEF2D may act as a key stimulus response regulator of microglia and is involved in the regulation of brain microhomeostasis. To uncover the molecular mechanism of MEF2D in the inflammatory system, in the present study, we investigated the global effect of MEF2D in activated microglia and explored its potential regulatory network. Methods Experiments with a recombinant lentiviral vector containing either shRNA or overexpressing MEF2D were performed in the murine microglial BV2 cell line. Transcriptome sequencing and global gene expression patterns were analysed in lipopolysaccharide-stimulated shMEF2D BV2 cells. Pro- and anti-inflammatory factors were assessed by Western blot, qPCR or ELISA, and microglial activity was assessed by phagocytosis and morphologic analysis. The direct binding of MEF2D to the promoter region of interferon regulatory factor 7 (IRF7) was tested by ChIP-qPCR. The interferon-stimulated genes (ISGs) were tested by qPCR. Results MEF2D actively participated in the inflammatory response of BV2 microglial cells. Stably expressed RNAi-induced silencing of MEF2D disrupted the microglial immune balance in two ways: (1) the expression of proinflammatory factors, such as NLRP3, IL-1β, and iNOS was promoted; and (2) the type-I interferon signalling pathway was markedly inhibited by directly modulating IRF7 transcription. In contrast, overexpression of MEF2D significantly reduced the expression of NLRP3 and iNOS under LPS stimulation and alleviated the level of immune stress in microglia. Conclusion These findings demonstrate that MEF2D plays an important role in regulating inflammatory homeostasis partly through transcriptional regulation of the type-I interferon signalling pathway.

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“…IFN-Is exert the antiviral and immunomodulatory activities by the induction of ISGs. IRF7 is the master transcriptional regulator of IFN-Is depended immune response (26,36). The regulatory mechanism of IRF7 in activated microglia is unclear.…”

Section: Discussionmentioning

confidence: 99%

Regulation of IFN-Is by MEF2D Promotes Inflammatory Homeostasis in Microglia

Lü

Wang

Nie

et al. 2021

Preprint

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Background Microglia play an essential role in the host defense of central nervous system. Transcription factor MEF2D is known to participate in stress regulation of various cells and is tightly triggered in microglia in vivo and in vitro. MEF2D is shown to bind at the promoter region of several cytokine genes in immune cells, and directly regulates inflammatory response, suggesting that MEF2D may act as a key stimulus response regulator of microglia and is involved in the regulation of brain micro-homeostasis. In order to uncover the molecular mechanism of MEF2D in inflammatory system, in the present study, we investigated the global effect of MEF2D in activated microglia, and explored its potential regulatory network. Methods Experiments of recombinant lentivirus vector of shRNA and specific MEF2D over-expression were performed in BV2 cells. Transcriptome sequencing and the global gene expression patterns were analyzed in lipopolysaccharide-stimulated shMEF2D BV2 cells. The pro- and anti-inflammatory factors were assessed by western blot, qPCR or ELISA, and microglia activity by phagocytosis and morphologic analysis. The directly binding of MEF2D to the promoter regions of IRF7 were tested by ChIP-qPCR and PCR. The ISGs were tested by qPCR. Results MEF2D was shown to actively participate in the inflammatory response of BV2 microglial cells. RNAi induced stable silence of MEF2D broke the immune balance of microglia, in two ways: (1) promoted the expression of pro-inflammatory factors, such as NLRP3, IL-1β, iNOS; and (2) markedly inhibited the type-I interferon signaling pathway by directly modulating the transcription of IRF7. On the contrary, overexpression of MEF2D significantly reduced the expression of NLRP3 and iNOS under LPS stimulation, and alleviated the level of immune stress in microglia. Conclusions These findings demonstrate that MEF2D plays an important role in the regulation of inflammatory homeostasis partly through transcriptional regulation of the IFN-Is response signaling pathway.

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IRF-7 triggers the interferon alarm

Cited by 3 publications

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Promoters of type I interferon genes from Atlantic salmon contain two main regulatory regions

Promoters of type I interferon genes from Atlantic salmon contain two main regulatory regions

Regulation of IFN-Is by MEF2D Promotes Inflammatory Homeostasis in Microglia

Regulation of IFN-Is by MEF2D Promotes Inflammatory Homeostasis in Microglia

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