A Nurr1/CoREST transrepression pathway attenuates neurotoxic inflammation in activated microglia and astrocytes

By Kaoru Saijo, Beate Winner, Christian T. Carson, J. Collier, Leah Boyer, Michael G. Rosenfeld, Fred H. Gage, Christopher K. Glass. Cell, 2009

914 citations recorded by the source corpus.

Nurr1, an orphan nuclear receptor, plays an essential role in the generation and maintenance of dopaminergic neurons in the brain. Rare mutations in Nurr1 are associated with familial Parkinson’s disease, but the underlying basis for this relationship has not been established. Here, we demonstrate that Nurr1 unexpectedly functions to inhibit expression of pro-inflammatory neurotoxic mediators in both microglia and astrocytes. Reduced Nurr1 expression results in exaggerated inflammatory responses in microglia that are further amplified by astrocytes, leading to the production of factors that cause death of tyrosine hydroxylase-expressing neurons. Nurr1 exerts anti-inflammatory effects by docking to NF-κB-p65 on target inflammatory gene promoters in a signal-dependent manner. Subsequently, Nurr1 recruits the CoREST corepressor complex, resulting in clearance of NF-κB-p65 and transcriptional repression. These studies suggest that Nurr1 protects against loss of dopaminergic neurons in Parkinson’s disease in part by limiting the production of neurotoxic mediators by microglia and astrocytes.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/791ec3a26a6c08628ef78e027c7566a9af916653

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Sofroniew
2. B. Barres
3. H. Vinters
4. F. Quintana
5. M. Linnerbauer
6. E. K. Kim
7. E. Choi
8. Christopher K. Glass

In Molecular Biology

1. M. Sofroniew
2. H. Vinters
3. A. Molofsky
4. E. K. Kim
5. E. Choi
6. Christopher K. Glass
7. D. Rowitch
8. C. Cunningham

Citations in the corpus

• Mechanisms Underlying Inflammation in Neurodegeneration (2010, neutral): “Separation of the different cell type components of the mixed culture system is most consistent with the interpretation that microglia are the primary initial responders to LPS and produce mediators such as TNF-a and IL-1b that activate astrocytes (Saijo et al., 2009).”
• Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia (2013, background): “Furthermore, recent evidence suggests that microglial and astroglial reactivity contribute to dopaminergic degeneration (Rappold and Tieu, 2010; Saijo et al., 2009; Zhang et al., 2005), and may mediate the progression of neurodegeneration in ASP (Fellner et al., 2011; Halliday and Stevens 2011).”
• Microglia in Alzheimer's Disease (2014, background): “Glass said that, in the inflammatory response process induced by bacterial endotoxin LPS, microglial cells were first activated, and then astrocytes accepted the immune signal of microglia and were passively activated; in both, mutual cooperation ultimately promoted the neuronal damage and degradati”
• Astrocytes: biology and pathology (2009, background): “Rare mutations in Nurr1 lead to familial Parkinson’s disease, and expression of Nurr1 in astrocytes suppresses production of potentially toxic molecules and protects against loss of dopaminergic neurons [203].”
• Astrocytes and disease: a neurodevelopmental perspective. (2012, background): “However, in the adult CNS, the Bergmann and Muller glia are thought to functionally resemble protoplasmic astrocytes in that they associate with and enwrap synapses and may act to modulate synaptic function (Saijo et al. 2009; Reichenbach et al. 2010).”
• Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells (2010, background): “A distinct type of signal-dependent negative feedback mediated by nuclear receptors has recently been described in microglia and astrocytes involving the orphan nuclear receptor NURR1 (Ref”
• Microglial cell origin and phenotypes in health and disease (2011, background): “Astrocytes also express TLR4, but at much lower levels compared with microglia, and they lack expression of CD14, which is a component of the high-affinity receptor for LP”
• Microglia: biology and pathology (2009, background): “The latter might include Nurr1 modulation in microglia and astrocytes [52, 153].”
• Innate immunity in the central nervous system. (2012, neutral): “The deciphering of microglial-astrocyte communication at the molecular level is still in its infancy but already shows promise for identifying interesting therapeutic targets (92, 93).”
• Compromised MAPK signaling in human diseases: an update (2015, background): “Indeed, Nurr1 recruits the CoREST corepressor complex to the transcription factor NF-κB, which acts at the promoters of proinflammatory genes, resulting in the release of NF-κB and repression of transcription (Saijo et al. 2009).”
• Astrocyte crosstalk in CNS inflammation (2020, background): “The chronic exposure to inflammatory signals and crosstalk with CNS-resident and nonresident cells alters astrocyte transcriptional programs, inducing “memory” responses stabilized by epigenetic modifications (Saijo et al., 2009; Wheeler et al., 2020b).”