RelB controls adaptive responses of astrocytes during sterile inflammation

Gupta, Angela; Waters, Michael R.; Biswas, Debolina D.; Brown, LaShardai N.; Surace, Michael; Floros, Constantinos; Siebenlist, Ulrich; Kordula, Tomasz

doi:10.1002/glia.23619

Cited by 22 publications

(38 citation statements)

References 49 publications

(97 reference statements)

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“…In another glial population involved in neuroinflammation, the astrocytes, the non-canonical NF-κB subunit RelB is crucial for the coordination of adaptive immunity; its upregulation in “tolerant” astrocytes is necessary for suppression of inflammatory signaling upon subsequent stimulation [ 44 ]. While we found no difference in expression of any of the NF-κB subunits (potential dimerization partners) in Shn2 KO mice, we did see a trend toward RelB mRNA reduction, suggesting Shn2-deficient astrocytes may be less able to appropriately suppress pro-inflammatory signaling.…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines

Murphy

Lawther

Webster

et al. 2020

J Neuroinflammation

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Background: High inflammation status despite an absence of known infection characterizes a subpopulation of people with schizophrenia who suffer from more severe cognitive deficits, less cortical grey matter, and worse neuropathology. Transcripts encoding factors upstream of nuclear factor kappa B (NF-κB), a major transcriptional activator for the synthesis of pro-inflammatory cytokines, are increased in the frontal cortex in schizophrenia compared to controls. However, the extent to which these changes are disease-specific, restricted to those with schizophrenia and high-neuroinflammatory status, or caused by loss of a key NF-κB inhibitor (HIVEP2) found in schizophrenia brain, has not been tested. Methods: Post-mortem prefrontal cortex samples were assessed in 141 human brains (69 controls and 72 schizophrenia) and 13 brains of wild-type mice and mice lacking HIVEP2 (6 wild-type, 7 knockout mice). Gene expression of pro-inflammatory cytokines and acute phase protein SERPINA3 was used to categorize high and low neuroinflammation biotype groups in human samples via cluster analysis. Expression of 18 canonical and noncanonical NF-κB pathway genes was assessed by qPCR in human and mouse tissue. Results: In humans, we found non-canonical upstream activators of NF-κB were generally elevated in individuals with neuroinflammation regardless of diagnosis, supporting NF-κB activation in both controls and people with schizophrenia when cytokine mRNAs are high. However, high neuroinflammation schizophrenia patients had weaker (or absent) transcriptional increases of several canonical upstream activators of NF-κB as compared to the high neuroinflammation controls. HIVEP2 mRNA reduction was specific to patients with schizophrenia who also had high neuroinflammatory status, and we also found decreases in NF-κB transcripts typically induced by activated microglia in mice lacking HIVEP2.

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Section: Discussionmentioning

confidence: 99%

Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines

Murphy

Lawther

Webster

et al. 2020

J Neuroinflammation

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“…RelB and p52 are also reported to function in driving tumor progression in glioma cell lines and is correlated with invasive potential (53). In addition, roles for RelB in reactive astrocytes (54) and microglia (55, 56) have been reported in the setting of chronic inflammation, such as can occur following brain injury or infection.…”

Section: Gliamentioning

confidence: 99%

Cellular Specificity of NF-κB Function in the Nervous System

2019

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Nuclear Factor Kappa B (NF-κB) is a ubiquitously expressed transcription factor with key functions in a wide array of biological systems. While the role of NF-κB in processes, such as host immunity and oncogenesis has been more clearly defined, an understanding of the basic functions of NF-κB in the nervous system has lagged behind. The vast cell-type heterogeneity within the central nervous system (CNS) and the interplay between cell-type specific roles of NF-κB contributes to the complexity of understanding NF-κB functions in the brain. In this review, we will focus on the emerging understanding of cell-autonomous regulation of NF-κB signaling as well as the non-cell-autonomous functional impacts of NF-κB activation in the mammalian nervous system. We will focus on recent work which is unlocking the pleiotropic roles of NF-κB in neurons and glial cells (including astrocytes and microglia). Normal physiology as well as disorders of the CNS in which NF-κB signaling has been implicated will be discussed with reference to the lens of cell-type specific responses.

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“…In glial cells, basal NF-κB activity is very low. For this reason, most studies have focused glial NF-κB in models of inflammation, injury, or disease (Dresselhaus and Meffert, 2019) where it is activated in its predominant form, the p50/RelA dimer (Kiebala et al, 2010;Simmons et al, 2016;Gupta et al, 2019). In inflammation, microglia activation results in the transcription of NF-κB-target genes, nitric oxide, IL-1β, and TNFα that in turn induce NF-κB signaling with consequent enhancement of inflammatory mediators that exacerbate neuronal cell death.…”

Section: Nf-κb Factors: Transcriptional Regulators Governing Neuroinfmentioning

confidence: 99%

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Bellucci

Bubacco

Longhena

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

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RelB controls adaptive responses of astrocytes during sterile inflammation

Cited by 22 publications

References 49 publications

Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines

Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines

Cellular Specificity of NF-κB Function in the Nervous System

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

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