RelB suppresses type I Interferon signaling in dendritic cells

Saha, Irene; Jaiswal, Hemant; Mishra, Richa; Nel, Hendrik J.; Schreuder, Jaring; Kaushik, Monika; Chauhan, Kuldeep Singh; Rawat, Bhupendra Singh; Thomas, Ranjeny; Naik, Shalin H.; Kumar, Himanshu; Tailor, Prafullakumar

doi:10.1016/j.cellimm.2020.104043

Cited by 16 publications

(11 citation statements)

References 28 publications

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“…The pregnancy recognition signal IFNT (type I interferon) participates in the implantation and establishment of pregnancy in ruminants (Spencer et al, 2016), and also induces expression of ISGs in the ovine maternal spleen during early pregnancy Wang et al, 2019). RelB is a negative regulator of the type I interferon signalling pathway in dendritic cells (Saha et al, 2020), and up-regulation of ISGs in the ovine maternal spleen may be related to the down-regulation of RelB in the spleen. RelB plays a key role in silencing or inhibiting the expression of the pro-inflammatory cytokines, and in a strong constitutive activation of RelB in decidual endothelial cells is beneficial for both avoiding pregnancy failure and immune tolerance to microorganisms during pregnancy (Masat et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Changes in nuclear factor kappa B components expression in the ovine spleen during early pregnancy

Hao¹,

Fang²,

Fang³

et al. 2022

J. Anim. Feed Sci.

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Section: Discussionmentioning

confidence: 99%

Changes in nuclear factor kappa B components expression in the ovine spleen during early pregnancy

Hao¹,

Fang²,

Fang³

et al. 2022

J. Anim. Feed Sci.

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“…Activation of canonical p65 signalling represses expression of anti-apoptotic genes following DNA damage (53). In addition, NIK- and RELB/p52-mediated pathways supress p65-dependent production of type I interferons and pro-inflammatory cytokines (54, 55). It is therefore possible that RELB/p52-mediated signalling in the absence of ATM provides a tolerance mechanism for limiting p65-driven pro-apoptotic responses.…”

Section: Discussionmentioning

confidence: 99%

Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

Bourseguin

Cheng

Talbot

et al. 2021

Preprint

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The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neurites. Pathological phagocytosis of neuronal processes by microglia has also been observed in multiple sclerosis, Alzheimer′s and progranulin deficiency, suggesting a common mechanism that promotes neuronal damage. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in Ataxia telangiectasia, potentially contributing to neurodegeneration.

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“…Packaging cells were transfected with retroviral vectors pMig-control-IRES-hCD8t and pMig-Irf8-IRES-hCD8t ( 38 , 39 ), and supernatant containing virus was collected after 48 h. For retroviral transduction, HapI-Irf8 5bp del cells (1 × 10 6 ) were incubated with Mig-control-IRES-hCD8t and Mig-Irf8-IRES-hCD8t supernatants of retroviruses expressing the truncated human CD8 surface marker by spinoculation (2,400 rpm, 33°C, 1 h) with 4 μg/ml Polybrene. One day postransduction, cell populations were analyzed by flow cytometry using an anti-human CD8-PE antibody (BioLegend, San Diego, CA, USA), and the human truncated CD8-expressing population was purified by magnet-activated cell separation using biotin-labeled anti-human CD8α antibody from BD Biosciences and streptavidin microbeads from Miltenyi Biotec ( 40 ). Sorted cells were infected with JEV at an MOI of 5 and harvested after 24 h of infection.…”

Section: Methodsmentioning

confidence: 99%

Lack of Interferon (IFN) Regulatory Factor 8 Associated with Restricted IFN-γ Response Augmented Japanese Encephalitis Virus Replication in the Mouse Brain

Tripathi

Rawat

Addya

et al. 2021

J Virol

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Interferon Regulatory Factor 8 (IRF8), a myeloid lineage transcription factor, emerges as an essential regulator for microglia activation. However, the precise role of IRF8 during Japanese encephalitis virus (JEV) infection in the brain remains elusive. Here we report that JEV infection enhances IRF8 expression in the infected mice brain. Comparative transcriptional profiling of whole-brain RNA analysis and validation by qRT-PCR reveals an impaired IFNγ and related gene expression in Irf8 knockout ( Irf8 -/- ) infected mice. Further, Ifnγ knockout ( Ifnγ -/- ) mice exhibit a reduced level of Irf8. Both Ifnγ -/- and Irf8 -/- mice exhibit significantly reduced levels of activated (CD11b + CD45 hi , CD11b + CD45 lo , Cd68, and CD86 ) and infiltrating immune cells (Ly6C + , CD4, and CD8) in the infected brain as compared to WT mice. However, a higher level of granulocyte cells (Ly6G + ) infiltration is evident in Irf8 -/- mice and the increased concentration of TNFα, IL6, MCP1 levels in the brain. Interestingly, neither Irf8 -/- nor Ifnγ -/- has conferred protection against lethal JEV challenge to mice and exhibits augmentation in JEV replication in the brain. The gain of function of Irf8 by overexpressing functional IRF8 in an IRF8 deficient cell line attenuates viral replication and enhances IFNγ production. Overall, we summarise that in the murine model of JEV encephalitis, IRF8 modulation affects JEV replication. We also evidence that lack of Irf8 affects immune cells abundance in circulation and the infected brain leading to a reduction in IFNγ level and increased viral load in the brain. Importance Microglial cells, the resident macrophages in the brain, play a vital role in Japanese encephalitis virus (JEV) pathogenesis. The deregulated activity of microglia can be lethal for the brain. Therefore, it is crucial to understand the regulators that drive microglia's phenotype changes and induce inflammation in the brain. Interferon regulatory factor 8 (IRF8) is a myeloid lineage transcription factor involved in microglial activation. However, the impact of IRF8 modulation on JEV replication remains elusive. Moreover, the pathways regulated by IRF8 to initiate and amplify pathological neuroinflammation are not well understood. Here, we demonstrated the effect of IRF8 modulation on JEV replication, microglial activation, and immune cells infiltration in the brain.

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RelB suppresses type I Interferon signaling in dendritic cells

Cited by 16 publications

References 28 publications

Changes in nuclear factor kappa B components expression in the ovine spleen during early pregnancy

Changes in nuclear factor kappa B components expression in the ovine spleen during early pregnancy

Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

Lack of Interferon (IFN) Regulatory Factor 8 Associated with Restricted IFN-γ Response Augmented Japanese Encephalitis Virus Replication in the Mouse Brain

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