Aryl Hydrocarbon Receptor Control of Adaptive Immunity
01 Oct 2013-Pharmacological Reviews (American Society for Pharmacology and Experimental Therapeutics)-Vol. 65, Iss: 4, pp 1148-1161
TL;DR: The aryl hydrocarbon receptor provides a molecular pathway through which environmental factors modulate the immune response in health and disease and the potential to target the AhR for therapeutic immunomodulation is discussed.
Abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that belongs to the family of basic helix-loop-helix transcription factors. Although the AhR was initially recognized as the receptor mediating the pathologic effects of dioxins and other pollutants, the activation of AhR by endogenous and environmental factors has important physiologic effects, including the regulation of the immune response. Thus, the AhR provides a molecular pathway through which environmental factors modulate the immune response in health and disease. In this review, we discuss the role of AhR in the regulation of the immune response, the source and chemical nature of AhR ligands, factors controlling production and degradation of AhR ligands, and the potential to target the AhR for therapeutic immunomodulation.
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TL;DR: Findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
Abstract: After upregulation of AHR in astrocytes by type I interferons, commensal-microbe-derived metabolites of dietary tryptophan act on astrocytes to suppress CNS inflammation.
856 citations
TL;DR: An overview of the physiological and pathophysiological roles of tryptophan metabolism is provided, focusing on the clinical potential and challenges associated with targeting this pathway.
Abstract: L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.
664 citations
TL;DR: It is reported that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis, and this pathway may guide new therapies for multiple sclerosis and other neurological disorders.
Abstract: Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1–3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.
601 citations
TL;DR: The role of AHR in autoimmune and neoplastic diseases of the central nervous system, with a special focus on the gut immune system, the gut–brain axis and the therapeutic potential of targeting A HR in neurological disorders are discussed.
Abstract: The environment, diet, microbiota and body’s metabolism shape complex biological processes in health and disease. However, our understanding of the molecular pathways involved in these processes is still limited. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that integrates environmental, dietary, microbial and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific and context-specific manner. In this Review, we summarize our current knowledge of AHR and the transcriptional programmes it controls in the immune system. Finally, we discuss the role of AHR in autoimmune and neoplastic diseases of the central nervous system, with a special focus on the gut immune system, the gut–brain axis and the therapeutic potential of targeting AHR in neurological disorders. By sensing environmental, dietary, microbial and metabolic cues, the ligand-activated transcription factor aryl hydrocarbon receptor controls complex transcriptional programmes that are relevant to autoimmune, neoplastic, metabolic and degenerative diseases.
581 citations
TL;DR: The role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer is discussed, as well as the potential opportunities and challenges of developing AhR-targeted therapeutics.
516 citations
Cites background from "Aryl Hydrocarbon Receptor Control o..."
...…in the control of functional FoxP3+ Treg cells, as indicated by the protective effects of AhR activation in experimental models of autoimmune disease like EAE (Quintana et al., 2008, 2010), colitis (Goettel et al., 2016), uveitis (Nugent et al., 2013), and diabetes (Kerkvliet et al., 2009)....
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...Indeed, AhR activation by ITE during EAE decreased CD86 and CD103 expression in DCs, reducing their ability to trigger proliferation and proinflammatory cytokine production in T cells, while increasing their production of TGF-b1 and IL-10....
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...Thus, the suppression of EAE by ITE administration likely involves multiple AhR-dependent mechanisms such as the suppression of effector T cells and CNS-resident cells by FoxP3+ Treg cells and Tr1 cells in addition to the modulation of DC function....
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...…including direct transactivation and the induction of epigenetic modifications that control Foxp3 transcription, and also through the modulation of DCs (Goettel et al., 2016; Kaye et al., 2016; Kerkvliet et al., 2009; Mezrich et al., 2010; Quintana et al., 2008; Singh et al., 2011, 2016)....
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...Moreover, ITE treatment increased the ability of DCs to expand Foxp3+ Treg cells and IL-10+ Tr1 cells and suppress EAE (Quintana et al., 2010)....
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References
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TL;DR: Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells and retroviral gene transfer of Foxp3 converts naïve T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+.
Abstract: Regulatory T cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Little is known, however, about the molecular mechanism of their development. Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells. Furthermore, retroviral gene transfer of Foxp3 converts naive T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+ regulatory T cells. Thus, Foxp3 is a key regulatory gene for the development of regulatory T cells.
8,082 citations
"Aryl Hydrocarbon Receptor Control o..." refers background in this paper
...FoxP3+ Tregs play a central role in the control of immune reactivity to self and non-self antigens, as shown by the inflammatory conditions associated with mutant FoxP3 in humans (Sakaguchi et al., 2010) and in mice (Fontenot et al., 2003; Hori et al., 2003; Wan and Flavell, 2007)....
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TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Abstract: The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.
7,888 citations
TL;DR: Recent advances that have been made by research into the role of TLR biology in host defense and disease are described.
Abstract: The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.
7,494 citations
"Aryl Hydrocarbon Receptor Control o..." refers background in this paper
...These features of AhR are reminiscent of the effects on immunity of Toll-like receptor (TLR) signaling triggered by self and non-self agonists (Kawai and Akira, 2010)....
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TL;DR: It is reported that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development and function and ectopic expression ofFoxp3 confers suppressor function on peripheral CD4-CD25− T cells.
Abstract: CD4+CD25+ regulatory T cells are essential for the active suppression of autoimmunity. Here we report that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development. The lethal autoimmune syndrome observed in Foxp3-mutant scurfy mice and Foxp3-null mice results from a CD4+CD25+ regulatory T cell deficiency and not from a cell-intrinsic defect of CD4+CD25- T cells. CD4+CD25+ regulatory T cells rescue disease development and preferentially expand when transferred into neonatal Foxp3-deficient mice. Furthermore, ectopic expression of Foxp3 confers suppressor function on peripheral CD4+CD25- T cells. Thus, Foxp3 is a critical regulator of CD4+CD25+ regulatory T cell development and function.
7,321 citations
"Aryl Hydrocarbon Receptor Control o..." refers background in this paper
...FoxP3+ Tregs play a central role in the control of immune reactivity to self and non-self antigens, as shown by the inflammatory conditions associated with mutant FoxP3 in humans (Sakaguchi et al., 2010) and in mice (Fontenot et al., 2003; Hori et al., 2003; Wan and Flavell, 2007)....
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TL;DR: Dendritic cells are antigen-presenting cells with a unique ability to induce primary immune responses and may be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response.
Abstract: Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.
6,758 citations
"Aryl Hydrocarbon Receptor Control o..." refers background in this paper
...After antigen uptake in the presence of DCmaturating stimuli, DCs upregulate the expression of the class II major histocompatibility complex, costimulatory molecules and cytokines that promote the polarization of T cells into specific populations (Banchereau et al., 2000; Guermonprez et al., 2002)....
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...the class II major histocompatibility complex, costimulatory molecules and cytokines that promote the polarization of T cells into specific populations (Banchereau et al., 2000; Guermonprez et al., 2002)....
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