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.
Astrocytes are the most abundant cell type in the central nervous system (CNS), performing complex functions in health and disease. It is now clear that multiple astrocyte subsets or activation ...states (plastic phenotypes driven by intrinsic and extrinsic cues) can be identified, associated to specific genomic programs and functions. The characterization of these subsets and the mechanisms that control them may provide unique insights into the pathogenesis of neurologic diseases, and identify potential targets for therapeutic intervention. In this article, we provide an overview of the role of astrocytes in CNS inflammation, highlighting recent discoveries on astrocyte subsets and the mechanisms that control them.
Astrocytes display functional and phenotypic heterogeneity across and within CNS regions under homeostatic conditions.CNS insults (trauma, infection, autoimmune inflammation, protein aggregates) induce a broad array of astrocyte activation states, poorly defined in terms of phenotype, function, and role in human pathology.Astrocyte activation during acute microbial infection is essential for pathogen clearance but can contribute to long-term neurological impairments.The plasticity of astrocytes and their ability to adopt either a proinflammatory or an anti-inflammatory phenotype could be targeted for therapeutic intervention.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by small molecules provided by the diet, microorganisms, metabolism, and pollutants. AhR is expressed ...by a number of immune cells, and thus AhR signaling provides a molecular pathway that integrates the effects of the environment and metabolism on the immune response. Studies have shown that AhR signaling plays important roles in the immune system in health and disease. As its activity is regulated by small molecules, AhR also constitutes a potential target for therapeutic immunomodulation. In this review we discuss the role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer, as well as the potential opportunities and challenges of developing AhR-targeted therapeutics.
AhR signaling integrates the effects of the environment and metabolism on the immune response. Gutiérrez-Vázquez and Quintana review the role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer, and discuss the potential opportunities and challenges of developing AhR-targeted therapeutics.
Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and ...sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting chromatin in microparticles released from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive chromatin on the surface of microparticles. Thus, extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism can contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.
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•Rapid anti-DNA antibody response, followed by SLE in Dnase1l3-deficient mice•Autoreactivity is repressed by circulating DNASE1L3 and is independent of STING•DNASE1L3 digests genomic DNA in microparticles released from apoptotic cells•DNASE1L3 prevents autoantibody binding to chromatin on microparticle surface
Extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism in mice and humans contributes to lupus, and the restoration of this mechanism may represent a therapeutic opportunity in the disease.
The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the ...CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.
Astrocyte Crosstalk in CNS Inflammation Linnerbauer, Mathias; Wheeler, Michael A.; Quintana, Francisco J.
Neuron (Cambridge, Mass.),
11/2020, Volume:
108, Issue:
4
Journal Article
Peer reviewed
Open access
Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated with specific genomic programs ...and functions. The advent of novel genomic technologies has enabled rapid progress in the characterization of astrocyte heterogeneity and its control by astrocyte interactions with other cells in the central nervous system (CNS). In this review, we provide an overview of the multifaceted roles of astrocytes in the context of CNS inflammation, highlighting recent discoveries on astrocyte subsets and their regulation. We explore mechanisms of crosstalk between astrocytes and other cells in the CNS in the context of neuroinflammation and neurodegeneration and discuss how these interactions shape pathological outcomes.
Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated with specific genomic programs and functions. The advent of novel genomic technologies has enabled rapid progress in the characterization of astrocyte heterogeneity and its control by astrocyte interactions with other cells in the central nervous system (CNS). In this review, we provide an overview of the multifaceted roles of astrocytes in the context of CNS inflammation, highlighting recent discoveries on astrocyte subsets and their regulation. We explore mechanisms of crosstalk between astrocytes and other cells in the CNS in the context of neuroinflammation and neurodegeneration and discuss how these interactions shape pathological outcomes.
Foxp3+ T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. ...Here we identified Foxp3+ T cells expressing the coinhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses proinflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT+ Treg cells as an activated Treg cell subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg-cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.
•TIGIT defines a distinct Foxp3+ Treg cell subset•TIGIT induces transcription and secretion of the effector molecule Fgl2 in Treg cells•TIGIT+ Treg cells suppress proinflammatory Th1 and Th17 not Th2 cell responses•Selective suppression by TIGIT+ Treg cells is Fgl2 dependent
Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple ...sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell-cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.
The Gut–CNS Axis in Multiple Sclerosis Kadowaki, Atsushi; Quintana, Francisco J.
Trends in neurosciences (Regular ed.),
08/2020, Volume:
43, Issue:
8
Journal Article
Peer reviewed
Open access
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS driven by the inflammatory activity of peripheral immune cells recruited to the CNS and by CNS-resident glial cells. MS ...pathogenesis has been linked to both genetic and environmental factors. In addition, the commensal flora have been shown to modulate immune processes relevant to MS pathogenesis. We discuss the effects of the gut microbiota on T cells and glial cells, and their relevance for the control of inflammation and neurodegeneration in MS. A better understanding of the gut–CNS axis will shed new light on the mechanisms of disease pathogenesis, and may help to guide the development of efficacious therapies for MS.
MS is an autoimmune inflammatory disease characterized by CNS inflammation and damage to myelin.T cells, B cells, and CNS-resident cells including astrocytes and microglia contribute to MS pathogenesis.MS pathogenesis has been linked to genetic and environmental factors, as well as to the gut microbiome.The microbiome modulates the differentiation and function of peripheral immune cells that control CNS inflammation.Microbial metabolites that reach the CNS can modulate the activity of resident glial cells such as astrocytes and microglia.
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