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Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells

Nature Reviews Immunology volume 10, pages 365–376 (2010)Cite this article

Subjects

Key Points

  • Members of the nuclear receptor superfamily of transcription factors have important roles in modulating the responses of macrophages, microglia and lymphocytes to pro-inflammatory signalling molecules.

  • The nuclear receptor co-repressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) co-repressor complexes function to maintain basal repression of a subset of genes that are activated by Toll-like receptors and other pro-inflammatory signalling pathways. These co-repressor complexes must be removed in response to inflammatory signals to allow maximal gene induction.

  • Peroxisome proliferator-activated receptor-γ (PPARγ) and liver X receptors antagonize a subset of inflammatory response genes by preventing the signal-dependent removal of NCoR and SMRT complexes.

  • Glucocorticoid receptor antagonizes a subset of inflammatory response genes by preventing interactions of nuclear factor-κB (NF-κB) with co-activators that are required in a gene-specific manner.

  • Glucocorticoid receptor and nuclear receptor related 1 (NURR1) antagonize a subset of inflammatory response genes by mediating the recruitment of co-repressor complexes to activator protein 1 (AP1) and NF-κB factors bound to target genes.

  • Emerging findings in T cells indicate that nuclear receptors use a combination of activation and repression pathways to regulate the differentiation and function of distinct helper T cell subsets.

Abstract

Members of the nuclear receptor superfamily of ligand-dependent transcription factors regulate diverse aspects of immunity and inflammation by both positively and negatively regulating gene expression. Here, we review recent studies providing insights into the distinct mechanisms that enable nuclear receptors to antagonize pro-inflammatory programmes of gene expression in macrophages and T cells by altering the turnover or recruitment of co-repressors and co-activators in a gene-specific manner. These nuclear receptor-dependent transrepression pathways are proposed to have roles in controlling the initiation, magnitude and duration of pro-inflammatory gene expression and are amenable to pharmacological manipulation.

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Figure 1: Examples of glucocorticoid receptor-mediated transrepression mechanisms involving tethering to AP1 or NF-κB transcription factors.
Figure 2: Mechanisms enabling rapid, high-magnitude responses to inflammatory stimuli.
Figure 3: Recruitment and signal-dependent turnover mechanisms controlling interactions of NCoR and SMRT co-repressor complexes with inflammatory responsive promoters.
Figure 4: Parallel sumoylation-dependent pathways mediate transrepression functions of PPARγ and LXRs.
Figure 5: Transrepression mechanisms that 'dismantle' active promoters.

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Acknowledgements

We thank W. Huang and A. Sullivan for their comments on the manuscript.

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  1. Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, GPL Room 217A, La Jolla, 92093-0651, California, USA

    Christopher K. Glass & Kaoru Saijo

  2. Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, GPL Room 217A, La Jolla, 92093-0651, California, USA

    Christopher K. Glass

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Glossary

Nuclear receptor

A ligand-dependent transcription factor characterized by a central DNA-binding domain and a carboxy-terminal ligand-binding domain. There are 48 different nuclear receptors expressed in humans, and 49 in mice, which regulate reproductive, developmental, homeostatic and immunological functions.

Glucocorticoid

A group of compounds that belongs to the corticosteroid family. These compounds can be naturally produced (hormones) or synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Many synthetic glucocorticoids are used in clinical medicine as anti-inflammatory drugs.

Steroid hormone

A small molecule derived from specific modifications of cholesterol that enable it to bind to and regulate the transcriptional functions of specific nuclear receptors. The major classes of steroid hormones are androgens, oestrogens, progestins, glucocorticoids and mineralocorticoids.

T helper 17 (TH17) cells

A subset of CD4+ TH cells that produce IL-17 and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-23 and IL-21, as well as the transcription factors RORγt and STAT3.

Pathogen-associated molecular pattern

A molecular pattern that is found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind Toll-like receptors.

Danger signals

Agents that alert the immune system to danger and thereby promote the generation of adaptive immune responses. Danger signals can be associated with microbial invaders (exogenous danger signals) or produced by damaged cells (endogenous danger signals).

Tethering

A mechanism by which a transcription factor interacts indirectly with a genomic region by interacting with other sequence-specific transcription factors.

M2 macrophage polarization

A phenotype that results when a macrophage is stimulated with IL-4 or IL-13, resulting in expression of arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.

Genome-wide location analysis

Studies in which chromatin immunoprecipitation of a transcription factor is coupled to parallel DNA sequencing to identify the binding sites of that transcription factor throughout the genome in a particular cell type.

LIN11–ISL1–MEC3 (LIM) domain

LIM domains are named after their discovery in the developmentally regulated transcription factors LIN11, ISL1 and MEC3. Each LIM domain consists of two tandem zinc fingers separated by two amino acids. LIM domains mediate protein–protein interactions and are frequently found in multiples.

Derepression

Reversal of a state of active transcriptional repression imposed by the binding of repressor or co-repressor complexes to a nearby gene.

E3 ubiquitin ligase

The enzyme that is required to attach the molecular tag ubiquitin to proteins that are destined for recognition by the proteasome complex.

Sumoylation

A post-translational modification of proteins that involves the covalent attachment of a small ubiquitin-related modifier (SUMO) molecule and regulates the interactions of those proteins with other macromolecules.

Purinergic receptors

A family of plasma membrane molecules that are involved in several known cellular functions, such as vascular reactivity, apoptosis and cytokine secretion.

Astrocyte

A type of glial cell that is found in the vertebrate brain and is named for its characteristic star-like shape. These cells provide both mechanical and metabolic support for neurons, thereby regulating the environment in which neurons function.

Microglia

Phagocytic cells of myeloid origin that are involved in the innate immune response in the central nervous system. Microglia are thought to be the major brain-resident macrophages.

Substantia nigra

A structure located in the midbrain that is important in reward behaviour, addiction and movement. Parkinson's disease is caused by the death of dopaminergic neurons in the substantia nigra.

α-synuclein

A neuronal protein of unknown function that is detected mainly in presynaptic terminals. It can aggregate to form insoluble fibrils known as Lewy bodies, which are observed in pathological conditions such as Parkinson's disease.

Regulatory T (TReg) cells

A population of CD4+ T cells that naturally express high levels of CD25 and the transcription factor FOXP3 and that have suppressive regulatory activity towards effector T cells and other immune cells in the periphery.

Gluconeogenic genes

Genes that encode regulatory proteins and enzymes that enable the liver to produce glucose under fasting conditions and maintain circulating glucose concentrations.

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Glass, C., Saijo, K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 10, 365–376 (2010). https://doi.org/10.1038/nri2748

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