The aryl hydrocarbon receptor: multitasking in the immune system.

The aryl hydrocarbon receptor (AhR), for many years almost exclusively studied by the pharmacology/toxicology field for its role in mediating the toxicity of xenobiotics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has more recently attracted the attention of immunologists. The evolutionary conservation of this transcription factor and its widespread expression in the immune system point to important physiological functions that are slowly being unraveled. In particular, the emphasis is now shifting from the role of AhR in the xenobiotic pathway toward its mode of action in response to physiological ligands. In this article, we review the current understanding of the molecular interactions and functions of AhR in the immune system in steady state and in the presence of infection and inflammation, with a focus on barrier organs such as the skin, the gut, and the lung.

Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses.

Intestinal Peyer's patches are essential lymphoid organs for the generation of T cell-dependent immunoglobulin A (IgA) for gut homeostasis. Through the use of interleukin 17 (IL-17) fate-reporter mice, we found here that endogenous cells of the TH17 subset of helper T cells in lymphoid organs of naive mice 'preferentially' homed to the intestines and were maintained independently of IL-23. In Peyer's patches, such TH17 cells acquired a follicular helper T cell (TFH cell) phenotype and induced the development of IgA-producing germinal center B cells. Mice deficient in TH17 cells failed to generate antigen-specific IgA responses, which provides evidence that TH17 cells are the crucial subset required for the production of high-affinity T cell-dependent IgA.

Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity.

Most tumours have an aberrantly activated lipid metabolism1,2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation3. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

A human cortical adaptive mutual inhibition circuit underlying competition for perceptual decision and repetition suppression reversal.

A model based on inhibitory coupling has been proposed to explain perceptual oscillations. This 'adapting reciprocal inhibition' model postulates that it is the strength of inhibitory coupling that determines the fate of competition between percepts. Here, we used an fMRI-based adaptation technique to reveal the influence of neighboring neuronal populations, such as reciprocal inhibition, in motion-selective hMT+/V5. If reciprocal inhibition exists in this region, the following predictions should hold: 1. stimulus-driven response would not simply decrease, as predicted by simple repetition-suppression of neuronal populations, but instead, increase due to the activity from adjacent populations; 2. perceptual decision involving competing representations, should reflect decreased reciprocal inhibition by adaptation; 3. neural activity for the competing percept should also later on increase upon adaptation. Our results confirm these three predictions, showing that a model of perceptual decision based on adapting reciprocal inhibition holds true. Finally, they also show that the net effect of the well-known repetition suppression phenomenon can be reversed by this mechanism.

Genetic deletion of hormone-sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet-induced obesity on memory.

Hormone-sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet-induced obesity. HSL-/-, HSL+/-, and HSL+/+ mice of either sex were fed high-fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild-type mice. CBF was positively correlated with lectin-stained vessel density. HSL deletion did not exacerbate HFD-induced microgliosis in the hippocampus and hypothalamus. HSL-/- mice showed preserved memory performance when compared to wild-type mice, and HSL deletion did not significantly aggravate HFD-induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD-induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet-induced obesity. While HSL-/- mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD-induced neuroinflammation and memory dysfunction.

Brain energy metabolism: A roadmap for future research.

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

Distinct oscillatory patterns differentiate between segregation and integration processes in perceptual grouping.

Recently, there has been a resurgence in experimental and conceptual efforts to understand how brain rhythms can serve to organize visual information. Oscillations can provide temporal structure for neuronal processing and form a basis for integrating information across brain areas. Here, we use a bistable paradigm and a data-driven approach to test the hypothesis that oscillatory modulations associate with the integration or segregation of visual elements. Spectral signatures of perception of bound and unbound configurations of visual moving stimuli were studied using magnetoencephalography (MEG) in ambiguous and unambiguous conditions. Using a 2 × 2 design, we were able to isolate correlates from visual integration, either perceptual or stimulus-driven, from attentional and ambiguity-related activity. Two frequency bands were found to be modulated by visual integration: an alpha/beta frequency and a higher frequency gamma-band. Alpha/beta power was increased in several early visual cortical and dorsal visual areas during visual integration, while gamma-band power was surprisingly increased in the extrastriate visual cortex during segregation. This points to an integrative role for alpha/beta activity, likely from top-down signals maintaining a single visual representation. On the other hand, when more representations have to be processed in parallel gamma-band activity is increased, which is at odds with the notion that gamma oscillations are related to perceptual coherence. These modulations were confirmed in intracranial EEG recordings and partially originate from distinct brain areas. Our MEG and stereo-EEG data confirms predictions of binding mechanisms depending on low-frequency activity for long-range integration and for organizing visual processing while refuting a straightforward correlation between gamma-activity and perceptual binding. PRACTITIONER POINTS: Distinct neurophysiological signals underlie competing bistable percepts. Increased alpha/beta activity correlate with visual integration while gamma correlates with segmentation. Ambiguous percepts drive alpha/beta activity in the posterior cingulate cortex.

Extracellular vesicles released from microglia after palmitate exposure impact brain function.

Dietary patterns that include an excess of foods rich in saturated fat are associated with brain dysfunction. Although microgliosis has been proposed to play a key role in the development of brain dysfunction in diet-induced obesity (DIO), neuroinflammation with cytokine over-expression is not always observed. Thus, mechanisms by which microglia contribute to brain impairment in DIO are uncertain. Using the BV2 cell model, we investigated the gliosis profile of microglia exposed to palmitate (200 µmol/L), a saturated fatty acid abundant in high-fat diet and in the brain of obese individuals. We observed that microglia respond to a 24-hour palmitate exposure with increased proliferation, and with a metabolic network rearrangement that favors energy production from glycolysis rather than oxidative metabolism, despite stimulated mitochondria biogenesis. In addition, while palmitate did not induce increased cytokine expression, it modified the protein cargo of released extracellular vesicles (EVs). When administered intra-cerebroventricularly to mice, EVs secreted from palmitate-exposed microglia in vitro led to memory impairment, depression-like behavior, and glucose intolerance, when compared to mice receiving EVs from vehicle-treated microglia. We conclude that microglia exposed to palmitate can mediate brain dysfunction through the cargo of shed EVs.

High-fat and High-sucrose Diet-induced Hypothalamic Inflammation Shows Sex Specific Features in Mice.

Hypothalamic inflammation underlies diet-induced obesity and diabetes in rodent models. While diet normalization largely allows for recovery from metabolic impairment, it remains unknown whether long-term hypothalamic inflammation induced by obesogenic diets is a reversible process. In this study, we aimed at determining sex specificity of hypothalamic neuroinflammation and gliosis in mice fed a fat- and sugar-rich diet, and their reversibility upon diet normalization. Mice were fed a 60%-fat diet complemented by a 20% sucrose drink (HFHSD) for 3 days or 24 weeks, followed by a third group that had their diet normalized for the last 8 weeks of the study (reverse diet group, RevD). We determined the expression of pro- and anti-inflammatory cytokines, and of the inflammatory cell markers IBA1, CD68, GFAP and EMR1 in the hypothalamus, and analyzed morphology of microglia (IBA-1+ cells) and astrocytes (GFAP+ cells) in the arcuate nucleus. After 3 days of HFHSD feeding, male mice showed over-expression of IL-13, IL-18, IFN-γ, CD68 and EMR1 and reduced expression of IL-10, while females showed increased IL-6 and IBA1 and reduced IL-13, compared to controls. After 24 weeks of HFHSD exposure, male mice showed a general depression in the expression of cytokines, with prominent reduction of TNF-α, IL-6 and IL-13, but increased TGF-ß, while female mice showed over-expression of IFN-γ and IL-18. Furthermore, both female and male mice showed some degree of gliosis after HFHSD feeding for 24 weeks. In mice of both sexes, diet normalization after prolonged HFHSD feeding resulted in partial neuroinflammation recovery in the hypothalamus, but gliosis was only recovered in females. In sum, HFHSD-fed mice display sex-specific inflammatory processes in the hypothalamus that are not fully reversible after diet normalization.

Density of Sphingosine-1-Phosphate Receptors Is Altered in Cortical Nerve-Terminals of Insulin-Resistant Goto-Kakizaki Rats and Diet-Induced Obese Mice.

Sphingosine-1-phosphate (S1P) is a phosphosphingolipid with pleiotropic biological functions. S1P acts as an intracellular second messenger, as well as extracellular ligand to five G-protein coupled receptors (S1PR1-5). In the brain, S1P regulates neuronal proliferation, apoptosis, synaptic activity and neuroglia activation. Moreover, S1P metabolism alterations have been reported in neurodegenerative disorders. We have previously reported that S1PRs are present in nerve terminals, exhibiting distinct sub-synaptic localization and neuromodulation actions. Since type 2 diabetes (T2D) causes synaptic dysfunction, we hypothesized that S1P signaling is modified in nerve terminals. In this study, we determined the density of S1PRs in cortical synaptosomes from insulin-resistant Goto-Kakizaki (GK) rats and Wistar controls, and from mice fed a high-fat diet (HFD) and low-fat-fed controls. Relative to their controls, GK rats showed similar cortical S1P concentration despite higher S1P levels in plasma, yet lower density of S1PR1, S1PR2 and S1PR4 in nerve-terminal-enriched membranes. HFD-fed mice exhibited increased plasma and cortical concentrations of S1P, and decreased density of S1PR1 and S1PR4. These findings point towards altered S1P signaling in synapses of insulin resistance and diet-induced obesity models, suggesting a role of S1P signaling in T2D-associated synaptic dysfunction.

Bacteriophages to control Vibrio alginolyticus in live feeds prior to their administration in larviculture.

AIMS: This study aimed to evaluate the efficiency of two phages [VB_VaC_TDDLMA (phage TDD) and VB_VaC_SRILMA (phage SRI)] alone and in a cocktail to control Vibrio alginolyticus in brine shrimp before their administration in larviculture. METHODS AND RESULTS: Phages were isolated from seawater samples and characterized by host spectrum, growth parameters, adsorption rate, genomic analysis, and inactivation efficiency. Both phages belong to the Caudoviricetes class and lack known virulence or antibiotic-resistance genes. They exhibit specificity, infecting only their host, V. alginolyticus CECT 521. Preliminary experiments in a culture medium showed that phage TDD (reduction of 5.8 log CFU ml-1 after 10 h) outperformed phage SRI (reduction of 4.6 log CFU ml-1 after 6 h) and the cocktail TDD/SRI (reduction of 5.2 log CFU ml-1 after 8 h). In artificial marine water experiments with Artemia franciscana, both single phage suspensions and the phage cocktail, effectively inactivated V. alginolyticus in culture water (reduction of 4.3, 2.1, and 1.9 log CFU ml-1 for phages TDD, SRI, and the phage cocktail, respectively, after 12 h) and in A. franciscana (reduction of 51.6%, 87.3%, and 85.3% for phages TDD, SRI, and the phage cocktail, respectively, after 24 h). The two phages and the phage cocktail did not affect A. franciscana natural microbiota or other Vibrio species in the brine shrimp. CONCLUSIONS: The results suggest that phages can safely and effectively control V. alginolyticus in A. franciscana prior to its administration in larviculture.

Mobile Data Gathering and Preliminary Analysis for the Functional Reach Test.

The functional reach test (FRT) is a clinical tool used to evaluate dynamic balance and fall risk in older adults and those with certain neurological diseases. It provides crucial information for developing rehabilitation programs to improve balance and reduce fall risk. This paper aims to describe a new tool to gather and analyze the data from inertial sensors to allow automation and increased reliability in the future by removing practitioner bias and facilitating the FRT procedure. A new tool for gathering and analyzing data from inertial sensors has been developed to remove practitioner bias and streamline the FRT procedure. The study involved 54 senior citizens using smartphones with sensors to execute FRT. The methods included using a mobile app to gather data, using sensor-fusion algorithms like the Madgwick algorithm to estimate orientation, and attempting to estimate location by twice integrating accelerometer data. However, accurate position estimation was difficult, highlighting the need for more research and development. The study highlights the benefits and drawbacks of automated balance assessment testing with mobile device sensors, highlighting the potential of technology to enhance conventional health evaluations.

The longitudinal impact of type 2 diabetes on brain gyrification.

Type 2 diabetes has an effect on brain structure, including cortical gyrification. The significance of these changes is better understood if assessed over time. However, there is a lack of studies assessing longitudinally the effect of this disease with complex aethology in gyrification. While changes in this feature have been associated mainly with genetic legacy, our study allowed to shed light on the effect of the variation of glycaemic profile over time in gyrification in this metabolic disease. In this longitudinal study, we analysed brain anatomical magnetic resonance images of 15 participants with type 2 diabetes and 13 healthy control participants to investigate the impact of this metabolic disease on the gyrification index over a 7-year period. We observed a significant interaction between time and group in six regions, four of which (left precentral gyrus, left gyrus rectus, left subcentral gyrus and sulci and right inferior temporal gyrus) showed an increase in gyrification in type 2 diabetes and a decrease in the control group and the two others (left pericallosal sulcus and right inferior frontal sulcus) the opposite pattern. The variation of the gyrification was correlated with the variation of the glycaemic profile. Following the interaction, the simple main effect of time in each group separately has shown that in the group with diabetes, there were more regions susceptible to alterations of gyrification. In sum, our results raise credit for the possibility that glycaemic control also might influence gyrification in type 2 diabetes.

Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance.

The pathophysiological mechanisms intersecting metabolic and neurodegenerative disorders include insulin resistance, which has a strong involvement of environmental factors. Besides central regulation of whole-body homeostasis, insulin in the central nervous system controls molecular signalling that is critical for cognitive performance, namely signalling through pathways that modulate synaptic transmission and plasticity, and metabolism in neurons and astrocytes. This review provides an overview on how insulin signalling in the brain might regulate brain energy metabolism, and further identified molecular mechanisms by which brain insulin resistance might impair synaptic fuelling, and lead to cognitive deterioration.

Fate mapping of IL-17-producing T cells in inflammatory responses.

Here we describe a reporter mouse strain designed to map the fate of cells that have activated interleukin 17A (IL-17A). We found that IL-17-producing helper T cells (T(H)17 cells) had distinct plasticity in different inflammatory settings. Chronic inflammatory conditions in experimental autoimmune encephalomyelitis (EAE) caused a switch to alternative cytokines in T(H)17 cells, whereas acute cutaneous infection with Candida albicans did not result in the deviation of T(H)17 cells to the production of alternative cytokines, although IL-17A production was shut off in the course of the infection. During the development of EAE, interferon-γ (IFN-γ) and other proinflammatory cytokines in the spinal cord were produced almost exclusively by cells that had produced IL-17 before their conversion by IL-23 ('ex-T(H)17 cells'). Thus, this model allows the actual functional fate of effector T cells to be related to T(H)17 developmental origin regardless of IL-17 expression.

Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.

Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.

Taurine and N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice.

Background: Obesity constitutes a risk factor for cognitive impairment. In rodent models, long-term exposure to obesogenic diets leads to hippocampal taurine accumulation. Since taurine has putative cyto-protective effects, hippocampal taurine accumulation in obese and diabetic models might constitute a counteracting response to metabolic stress. Objective: We tested the hypothesis that treatment with taurine or with N-acetylcysteine (NAC), which provides cysteine for the synthesis of taurine and glutathione, prevent high-fat diet (HFD)-associated hippocampal alterations and memory impairment. Methods: Female mice were fed either a regular diet or HFD. Some mice had access to 3%(w/v) taurine or 3%(w/v) NAC in the drinking water. After 2 months, magnetic resonance spectroscopy (MRS) was used to measure metabolite profiles. Memory was assessed in novel object and novel location recognition tests. Results: HFD feeding caused memory impairment in both tests, and reduced concentration of lactate, phosphocreatine-to-creatine ratio, and the neuronal marker N-acetylaspartate in the hippocampus. Taurine and NAC prevented HFD-induced memory impairment and N-acetylaspartate reduction. NAC, but not taurine, prevented the reduction of lactate and phosphocreatine-to-creatine ratio. MRS revealed NAC/taurine-induced increase of hippocampal glutamate and GABA levels. Conclusion: NAC and taurine can prevent memory impairment, while only NAC prevents alterations of metabolite concentrations in HFD-exposed female mice.

The role of early functional neuroimaging in predicting neurodevelopmental outcomes in neonatal encephalopathy.

Reliably assessing the early neurodevelopmental outcomes in infants with neonatal encephalopathy (NE) is of utmost importance to advise parents and implement early and personalized interventions. We aimed to evaluate the accuracy of neuroimaging modalities, including functional magnetic resonance imaging (fMRI) in predicting neurodevelopmental outcomes in NE. Eighteen newborns with NE due to presumed perinatal asphyxia (PA) were included in the study, 16 of whom underwent therapeutic hypothermia. Structural magnetic resonance imaging (MRI), and fMRI during passive visual, auditory, and sensorimotor stimulation were acquired between the 10th and 14th day of age. Clinical follow-up protocol included visual and auditory evoked potentials and a detailed neurodevelopmental evaluation at 12 and 18 months of age. Infants were divided according to sensory and neurodevelopmental outcome: severe, moderate disability, or normal. Structural MRI findings were the best predictor of severe disability with an AUC close to 1.0. There were no good predictors to discriminate between moderate disability versus normal outcome. Nevertheless, structural MRI measures showed a significant correlation with the scores of neurodevelopmental assessments. During sensorimotor stimulation, the fMRI signal in the right hemisphere had an AUC of 0.9 to predict absence of cerebral palsy (CP). fMRI measures during auditory and visual stimulation did not predict sensorineural hearing loss or cerebral visual impairment. CONCLUSION: In addition to structural MRI, fMRI with sensorimotor stimulation may open the gate to improve the knowledge of neurodevelopmental/motor prognosis if proven in a larger cohort of newborns with NE. WHAT IS KNOWN: • Establishing an early, accurate neurodevelopmental prognosis in neonatal encephalopathy remains challenging. • Although structural MRI has a central role in neonatal encephalopathy, advanced MRI modalities are gradually being explored to optimize neurodevelopmental outcome knowledge. WHAT IS NEW: • Newborns who later developed cerebral palsy had a trend towards lower fMRI measures in the right sensorimotor area during sensorimotor stimulation. • These preliminary fMRI results may improve future early delineation of motor prognosis in neonatal encephalopathy.

Hysteresis reveals a happiness bias effect in dynamic emotion recognition from ambiguous biological motion.

Considering the nonlinear dynamic nature of emotion recognition, it is believed to be strongly dependent on temporal context. This can be investigated by resorting to the phenomenon of hysteresis, which features a form of serial dependence, entailed by continuous temporal stimulus trajectories. Under positive hysteresis, the percept remains stable in visual memory (persistence) while in negative hysteresis, it shifts earlier (adaptation) to the opposite interpretation. Here, we asked whether positive or negative hysteresis occurs in emotion recognition of inherently ambiguous biological motion, while testing for the controversial debate of a negative versus positive emotional bias. Participants (n = 22) performed a psychophysical experiment in which they were asked to judge stimulus transitions between two emotions, happiness and sadness, from an actor database, and report perceived emotion across time, from one emotion to the opposite as physical cues were continuously changing. Our results reveal perceptual hysteresis in ambiguous emotion recognition, with positive hysteresis (visual persistence) predominating. However, negative hysteresis (adaptation/fatigue) was also observed in particular in the direction from sadness to happiness. This demonstrates a positive (happiness) bias in emotion recognition in ambiguous biological motion recognition. Finally, the interplay between positive and negative hysteresis suggests an underlying competition between visual persistence and adaptation mechanisms during ambiguous emotion recognition.

Plasma Galectin-4 Levels Are Increased after Stroke in Mice and Humans.

Epidemiological studies have associated plasma galectin-4 (Gal-4) levels with prevalent and incident diabetes, and with an increased risk of coronary artery disease. To date, data regarding possible associations between plasma Gal-4 and stroke are lacking. Using linear and logistic regression analyses, we tested Gal-4 association with prevalent stroke in a population-based cohort. Additionally, in mice fed a high-fat diet (HFD), we investigated whether plasma Gal-4 increases in response to ischemic stroke. Plasma Gal-4 was higher in subjects with prevalent ischemic stroke, and was associated with prevalent ischemic stroke (odds ratio 1.52; 95% confidence interval 1.01-2.30; p = 0.048) adjusted for age, sex, and covariates of cardiometabolic health. Plasma Gal-4 increased after experimental stroke in both controls and HFD-fed mice. HFD exposure was devoid of impact on Gal-4 levels. This study demonstrates higher plasma Gal-4 levels in both experimental stroke and in humans that experienced ischemic stroke.