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      Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and CNS inflammation via the aryl hydrocarbon receptor


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          Astrocytes play important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-I) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from multiple sclerosis (MS) patients. IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) and suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered IFN-β are partly mediated by AhR. Dietary tryptophan is metabolized by the gut microbiota into AhR agonists that act on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate (I3S), indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld), or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AhR agonists were decreased. These findings suggest that IFN-I produced in the CNS act in combination with metabolites derived from dietary tryptophan by the gut flora to activate AhR signaling in astrocytes and suppress CNS inflammation.

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          Most cited references36

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          The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.
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            Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis.

            Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-γ and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A-producing CD4(+) T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro- and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.
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              Diversity of astrocyte functions and phenotypes in neural circuits.

              Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit-specific roles in health and disease.

                Author and article information

                Nat Med
                Nat. Med.
                Nature medicine
                14 April 2016
                09 May 2016
                June 2016
                09 November 2016
                : 22
                : 6
                : 586-597
                [1 ]Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
                [2 ]Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
                [3 ]Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia
                [4 ]Neuroimmunology Research Lab, Center for Excellence in Neuromics CRCHUM, Université de Montréal, Montréal, QC, Canada
                [5 ]Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA
                [6 ]Molecular Biology Service and MS Unit, University of Sevilla, Sevilla, Spain
                [7 ]Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
                [8 ]Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [9 ]Metabolite Profiling Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [10 ]Institute of Neuropathology, University of Freiburg, Freiburg, Germany
                Author notes
                [* ]Correspondence to: Francisco J. Quintana ( fquintana@ 123456rics.bwh.harvard.edu ), Ann Romney Center for Neurologic Diseases, Harvard Medical School, Boston, MA, USA

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