Aryl hydrocarbon receptor AND multiple sclerosis

Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative L-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways...

Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination in mouse models of MS. During remyelination, myeloid cells upregulated the expression of IL4I1. Conditionally knocking out IL4I1 in myeloid cells impaired remyelination efficiency. Mice lacking IL4I1 expression exhibited a reduction in the AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, in remyelinating lesions...

Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling...

The aryl hydrocarbon receptor (AHR) is a sensor of low-molecular-weight molecule signals that originate from environmental exposures, the microbiome, and host metabolism. Building upon initial studies examining anthropogenic chemical exposures, the list of AHR ligands of microbial, diet, and host metabolism origin continues to grow and has provided important clues as to the function of this enigmatic receptor. The AHR has now been shown to be directly involved in numerous biochemical pathways that influence host homeostasis, chronic disease development, and responses to toxic insults...

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the central nervous system (CNS). Although studies have demonstrated that microglia facilitate remyelination in demyelinating diseases, the underlying mechanisms are still not fully characterized. We found that aryl hydrocarbon receptor (AhR), an environment sensor, was upregulated within the corpus callosum in the cuprizone model of CNS demyelination, and upregulated AhR was mainly confined to microglia. Deletion of AhR in adult microglia inhibited efficient remyelination...

Interleukin (IL)-10 is a main player in peripheral immune tolerance, the physiological mechanism preventing immune reactions to self/harmless antigens. Here, we investigate IL-10-induced molecular mechanisms generating tolerogenic dendritic cells (tolDC) from monocytes. Using genomic studies, we show that IL-10 induces a pattern of accessible enhancers exploited by aryl hydrocarbon receptor (AHR) to promote expression of a set of core genes. We demonstrate that AHR activity occurs downstream of IL-10 signaling in myeloid cells and is required for the induction of tolerogenic activities in DC...

Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR's precise function in T lymphocytes, the orchestrators of MS, has not been described...

Nearly a quarter of the total number of deaths in the world are caused by unhealthy living or working environments. Therefore, we consider it significant to introduce the effect of a widely distributed component of air/water/food-source contaminants, polycyclic aromatic hydrocarbons (PAHs), on the human body, especially on immunity in this review. PAHs are a large class of organic compounds containing two or more benzene rings. PAH exposure could occur in most people through breath, smoke, food, and direct skin contact, resulting in both cellular immunosuppression and humoral immunosuppression...

BACKGROUND: Dysregulation of gut microbiota-associated tryptophan metabolism has been observed in patients with multiple sclerosis. However, defining direct mechanistic links between this apparent metabolic rewiring and individual constituents of the gut microbiota remains challenging. We and others have previously shown that colonization with the gut commensal and putative probiotic species, Lactobacillus reuteri, unexpectedly enhances host susceptibility to experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis...

The aryl hydrocarbon receptor (AhR), discovered 46 years ago, is a transcript factor member of the basic helix-loop-helix Per-ARNT-SIM (bHLH-PAS) family deeply implicated in health and diseases, and is traditionally associated with the metabolism of xenobiotic ligands. Recently, multiple and structurally diverse ingredients including amino acid metabolites, polyphenols, flavonoids, polyhydroxyalkanoates, polychlorinated biphenyls, and, triarylmethanes have been evaluated as AhR potential ligands, and there is increasing attention on AhR as an appealing target in various cancers, autoimmune disorders, inflammatory bowel diseases, rheumatoid arthritis and multiple sclerosis...

Melatonin (MT), a neurohormone with immunomodulatory properties, is one of the metabolites produced in the brain from tryptophan (TRP) that has already strong links with the neuropathogenesis of Multiple sclerosis (MS). However, the exact molecular mechanisms behind that are not fully understood. There is some evidence showing that MS and MT are interconnected via different pathways: Relapses of MS has a direct correlation with a low level of MT secretion and a growing body of evidence suggest that MT be therapeutic in Experimental Autoimmune Encephalomyelitis (EAE, a recognise animal model of MS) severity...

Background: The essential amino acid, tryptophan, is predominantly metabolised through the kynurenine pathway (KP) to generate kynurenine, an aryl-hydrocarbon receptor (AhR) pro-ligand that exerts its effects in a ligand-dependent manner. Interaction between kynurenine and the AhR is an effector mechanism of immunosuppression. We previously found that the KP is involved in multiple sclerosis (MS) disease progression. We postulated that AhR activation by kynurenine might be neuroprotective by encouraging differentiation of Tregs...

For decades, activation of Aryl Hydrocarbon Receptor (AhR) was excluded from consideration as a therapeutic approach due to the potential toxic effects of AhR ligands and the induction of the cytochrome P450 enzyme, Cyp1a1, following AhR activation. However, it is now understood that AhR activation not only serves as an environmental sensor that regulates the effects of environmental toxins, but also as a key immunomodulator where ligands induce a variety of cellular and epigenetic mechanisms to attenuate inflammation...

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-β/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance...

The biological mechanism by which maternal undernutrition increases the metabolic disorder risk of skeletal muscles in offspring is not fully understood. We hypothesize that maternal intake restriction influences metabolic signals in the skeletal muscles of offspring via a glucagon-mediated pathway. Twenty-four pregnant goats were assigned to the control group (100% of the nutrients requirement, n  = 12) and restricted group (60% of the control feed allowance from pregnant days 45 to 100, n  = 12). Blood and L ongissimus thoracis muscle were sampled from dams (100 d of gestation), fetuses (100 d of gestation), and kids (90 d after birth) in each group...

OBJECTIVE: To evaluate the aryl hydrocarbon receptor (AHR)-dependent transforming growth factor alpha (TGF-α)/vascular endothelial growth factor B (VEGF-B) ratio, which regulates the effects of metabolic, dietary, and microbial factors on acute and chronic CNS inflammation, as a potential marker in multiple sclerosis (MS). METHODS: TGF-α, VEGF-B, and AHR agonistic activity were determined in serum of 252 patients with relapsing-remitting (RR) MS, primary and secondary progressive MS, as well as during active disease (clinically isolated syndrome [CIS] and RRMS relapse)...

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE. METHODS: C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55 ) to establish the EAE model...

Gut immune cells have been increasingly appreciated as important players in the central nervous system (CNS) autoimmunity in animal models of multiple sclerosis (MS). Among the gut immune cells, innate lymphoid cell type 3 (ILC3) is of special interest in MS research, as they represent the innate cell counterpart of the major pathogenic cell population in MS, i.e. T helper (Th)17 cells. Importantly, these cells have been shown to stimulate regulatory T cells (Treg) and to counteract pathogenic Th17 cells in animal models of autoimmune diseases...

The edible cyanobacterium Spirulina platensis and its chief biliprotein C-Phycocyanin have shown protective activity in animal models of diverse human health diseases, often reflecting antioxidant and anti-inflammatory effects. The beneficial effects of C-Phycocyanin seem likely to be primarily attributable to its covalently attached chromophore Phycocyanobilin (PCB). Within cells, biliverdin is generated from free heme and it is subsequently reduced to bilirubin. Although bilirubin can function as an oxidant scavenger, its potent antioxidant activity reflects its ability to inactivate some isoforms of NADPH oxidase...

In the last decade, emerging evidence has reported correlations between the gut microbiome and human health and disease, including those affecting the brain. We performed a systematic assessment of the available literature focusing on gut bacterial metabolites and their associations with diseases of the central nervous system (CNS). The bacterial metabolites short-chain fatty acids (SCFAs) as well as non-SCFAs like amino acid metabolites (AAMs) and bacterial amyloids are described in particular. We found significantly altered SCFA levels in patients with autism spectrum disorder (ASD), affective disorders, multiple sclerosis (MS) and Parkinson's disease (PD)...