Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an extended polyglutamine repeat in the N terminus of the Huntingtin protein (HTT). Reactive microglia and elevated cytokine ...levels are observed in the brains of HD patients, but the extent to which neuroinflammation results from extrinsic or cell-autonomous mechanisms in microglia is unknown. Using genome-wide approaches, we found that expression of mutant Huntingtin (mHTT) in microglia promoted cell-autonomous pro-inflammatory transcriptional activation by increasing the expression and transcriptional activities of the myeloid lineage-determining factors PU.1 and C/EBPs. We observed elevated levels of PU.1 and its target genes in the brains of mouse models and individuals with HD. Moreover, mHTT-expressing microglia exhibited an increased capacity to induce neuronal death ex vivo and in vivo in the presence of sterile inflammation. These findings suggest a cell-autonomous basis for enhanced microglia reactivity that may influence non-cell-autonomous HD pathogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Microglia and astrocytes play essential roles in the maintenance of homeostasis within the central nervous system, but mechanisms that control the magnitude and duration of responses to infection and ...injury remain poorly understood. Here, we provide evidence that 5-androsten-3β,17β-diol (ADIOL) functions as a selective modulator of estrogen receptor (ER)β to suppress inflammatory responses of microglia and astrocytes. ADIOL and a subset of synthetic ERβ-specific ligands, but not 17β-estradiol, mediate recruitment of CtBP corepressor complexes to AP-1-dependent promoters, thereby repressing genes that amplify inflammatory responses and activate Th17 T cells. Reduction of ADIOL or ERβ expression results in exaggerated inflammatory responses to TLR4 agonists. Conversely, the administration of ADIOL or synthetic ERβ-specific ligands that promote CtBP recruitment prevents experimental autoimmune encephalomyelitis in an ERβ-dependent manner. These findings provide evidence for an ADIOL/ERβ/CtBP-transrepression pathway that regulates inflammatory responses in microglia and can be targeted by selective ERβ modulators.
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► ERβ functions as an ADIOL receptor in the brain to repress inflammatory responses ► ADIOL production is regulated by inflammatory signaling ► ADIOL induces ERβ recruitment of CtBP corepressors to proinflammatory promoters ► Synthetic ADIOL-like ERβ modulators suppress disease in a mouse model of MS
Inflammation is associated with many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss ...inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neuronal dysfunction and death. Although inducers of inflammation may be generated in a disease-specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators. A major unanswered question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease.
Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia ...phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain. Substantial subsets of these genes exhibited altered expression in neurodegenerative and behavioral diseases and were associated with noncoding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human brain diseases.
Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic ...marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A (
Tcf3) in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are premarked by the poised or active enhancer mark H3K4me1 in multipotent progenitors. Thus, in hematopoietic progenitors, multilineage priming of enhancer elements precedes commitment to the lymphoid or myeloid cell lineages.
► Long -term culture of multipotent hematopoietic progenitors ► The E2A proteins play a causative role in initiating B cell development ► Enhancers are primed for lineage plasticity in multipotent progenitors by H3K4me1
Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its ...removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.
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•Macrophage NCoR KO mice are protected from HFD-induced insulin resistance•NCoR deletion results in a paradoxical hyporesponsiveness to TLR4 signaling•Derepression of LXRs results in increased anti-inflammatory ω3 fatty acids•ω3 fatty acids inhibit enhancer/promoter activation at hyporesponsive genes
Loss of NcoR unexpectedly leads to an anti-inflammatory phenotype in mice, along with increased insulin sensitivity, due to derepression of LXR-regulated pathways. Activation of LXR stimulates production of anti-inflammatory palmitoleic and omega 3 fatty acids.
Signaling by nuclear receptors Sever, Richard; Glass, Christopher K
Cold Spring Harbor perspectives in biology,
2013-Mar-01, 2013-03-01, 20130301, Letnik:
5, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Nuclear receptors are activated by lipid-soluble signals (e.g., steroid hormones) that cross the plasma membrane. Once activated, most function as transcription factors to control gene expression for ...numerous biological processes.
The peroxisome proliferator-activated receptors (PPARα, -γ, and -β/δ) are nuclear receptors with distinct patterns of expression in many cell types both within and outside the immune system. PPAR ...ligands have anti-inflammatory activity in a variety of mouse models for acute and chronic inflammation. In macrophages, PPARγ ligands repress expression of a subset of Toll-like receptor (TLR) target genes by a molecular mechanism termed ligand-dependent transrepression. In chronic inflammation, ligand-bound PPARα represses production of IFNγ and IL-17 by CD4+ T cells, and PPARγ ligands modulate dendritic cell function to elicit the development of anergic CD4+ T cells. PPAR ligands also repress expression of cell adhesion molecules on endothelial cells and the secretion of chemokines by epithelial and other cells, decreasing the recruitment of leukocytes to the site of inflammation. The anti-inflammatory activity of PPAR ligands in mouse models suggests their possible use for treating human inflammatory and autoimmune diseases.
Inflammation influences cancer development, progression, and the efficacy of cancer treatments, yet the mechanisms by which immune signaling drives alterations in the cancer cell transcriptome remain ...unclear. Using ChIP-seq, RNA-seq, and GRO-seq, here we demonstrate a global overlap in the binding of tumor-promoting p53 mutants and the master proinflammatory regulator NFκB that drives alterations in enhancer and gene activation in response to chronic TNF-α signaling. We show that p53 mutants interact directly with NFκB and that both factors impact the other's binding at diverse sets of active enhancers. In turn, the simultaneous and cooperative binding of these factors is required to regulate RNAPII recruitment, the synthesis of enhancer RNAs, and the activation of tumor-promoting genes. Collectively, these findings establish a mechanism by which chronic TNF-α signaling orchestrates a functional interplay between mutant p53 and NFκB that underlies altered patterns of cancer-promoting gene expression.Inflammation is known to affect cancer development, yet the mechanisms by which immune signaling drives transformation remain unclear. Here, the authors provide evidence that chronic TNF-α signaling promotes the enhancer binding and transcriptional interplay between mutant p53 and NFκB.
Monocytes are progenitors to macrophages and a subclass of dendritic cells (monocyte-derived dendritic cells, MoDCs), but they also act as circulating sensors that respond to environmental changes ...and disease. Technological advances have defined the production of classical monocytes in the bone marrow through the identification of lineage-determining transcription factors (LDTFs) and have proposed alternative routes of differentiation. Monocytes released into the circulation can be recruited to tissues by specific chemoattractants where they respond to sequential niche-specific signals that determine their differentiation into terminal effector cells. New aspects of monocyte biology in the circulation are being revealed, exemplified by the influence of cancer on the systemic alteration of monocyte subset abundance and transcriptional profiles. These changes can act to enhance the metastatic spread of primary cancers and may offer therapeutic opportunities.
Mammalian monocyte development in the bone marrow from hematopoietic stem cells is driven by evolving and dynamic genomic enhancer landscapes and sequential binding of LDTFs.Monocyte fates are highly diverse; their plasticity and niche-specific regulation are beginning to be revealed in the contexts of homeostasis, inflammation, and cancer.Murine models of liver injury reveal that the interactions of monocytes with liver sinusoidal cells can lead to sequential alterations of genomic enhancer landscapes that ultimately drive Kupffer cell-specific expression of enhancers and genes.Murine models of genetic fate mapping, combined with studies of human cancers using single-cell transcriptome and proteome analysis, as well as bioinformatic-inferred algorithms for mapping trajectories of cellular differentiation, demonstrate that the tumor-associated macrophage phenotype is driven by tumor-specific features, regardless of their origin from monocytes or from yolk sac-derived tissue-resident monocytes.
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