Dendritic cells (DCs) are potent antigen-presenting cells (APCs), which sample the exogenous and endogenous cues to control adaptive immunity, balancing effector and regulatory components of the ...immune response. Multiple subsets of DCs, such as plasmacytoid and conventional DCs, have been defined based on specific phenotypic markers, functions and regulatory transcriptional programs. Tolerogenic DCs (tolDCs) have been functionally defined based on their ability to expand the regulatory T-cell compartment and suppress immune responses. However, it is still unclear whether tolDCs represent a homogeneous population, a specific DC subset and/or a heterogeneous collection of DC activation/maturation states. The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) has been shown to control transcriptional programs associated to tolDCs. In this review, we discuss the role of AHR in the control of tolDCs, and also AHR-targeted approaches for the therapeutic induction of tolDCs in autoimmune diseases and allergy.
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection ...followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.
Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells
. Genetic variants that are associated with the function of DCs have been linked to autoimmune ...disorders
, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.
Free-ranging non-human primates (NHP) can live in anthropized areas or urban environments in close contact with human populations. This condition can enable the emergence and transmission of ...high-impact zoonotic pathogens. For the first time, we detected a coinfection of the yellow fever (YF) virus with
Toxoplasma gondii
in a free-ranging NHP in a highly urbanized area of a metropolis in Brazil. Specifically, we observed this coinfection in a black-tufted marmoset found dead and taken for a necropsy by the local health surveillance service. After conducting an epidemiological investigation, characterizing the pathological features, and performing molecular assays, we confirmed that the marmoset developed an acute fatal infection caused by
T. gondii
in coinfection with a new YF virus South American-1 sub-lineage. As a result, we have raised concerns about the public health implications of these findings and discussed the importance of diagnosis and surveillance of zoonotic agents in urbanized NHPs. As competent hosts of zoonotic diseases such as YF and environmental sentinels for toxoplasmosis, NHPs play a crucial role in the One Health framework to predict and prevent the emergence of dangerous human pathogens.
Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of ...the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.
Despite recent advances in the treatment of neonatal hypoxic-ischemic encephalopathy (HIE) using therapeutic hypothermia, at least 30% of the cooled infants will die or have moderate/severe ...neurological disability. Umbilical cord blood cells (UCBCs), which are readily available at birth, have been shown to reduce sensorimotor and/or cognitive impairments in several models of brain damage, representing a promising option for the treatment of neurological diseases. In this review, we discuss recent preclinical studies that assessed the effects of UCBC transplantation in the Rice-Vannucci animal model of HIE. We also review the possible cell types and mechanisms involved in the therapeutic effect of UCBC transplantation, including neuroprotection, immunomodulation, and stimulation of neural plasticity and regeneration. In addition, we discuss how neuroimaging methods, such as bioluminescence imaging, nuclear-medicine imaging, or magnetic resonance imaging, could be used to evaluate the biodistribution of UCBCs in both preclinical and clinical studies.
Intracerebral hemorrhage is the most serious complication of anticoagulant therapy but the effects of different types of oral anticoagulants on the expansion of these hemorrhages are still unclear. ...Clinical studies have revealed controversial results; more robust and long-term clinical evaluations are necessary to define their outcomes. An alternative is to test the effect of these drugs in experimental models of intracerebral bleeding induced in animals.
To test new oral anticoagulants (dabigatran etexilate, rivaroxaban, and apixaban) in an experimental model of intracerebral hemorrhage induced by collagenase injection into the brain striatum of rats. Warfarin was used for comparison.
Ex vivo anticoagulant assays and an experimental model of venous thrombosis were employed to determine the doses and periods of time required for the anticoagulants to achieve their maximum effects. Subsequently, volumes of brain hematoma were evaluated after administration of the anticoagulants, using these same parameters. Volumes of brain hematoma were evaluated by magnetic resonance imaging, H&E (hematoxylin and eosin) staining, and Evans blue extravasation. Neuromotor function was assessed by the elevated body swing test.
The new oral anticoagulants did not increase intracranial bleeding compared with control animals, while warfarin markedly favored expansion of the hematomas, as revealed by magnetic resonance imaging and H&E staining. Dabigatran etexilate caused a modest but statistically significant increase in Evans blue extravasation. We did not observe significant differences in elevated body swing tests among the experimental groups. The new oral anticoagulants may provide a better control over a brain hemorrhage than warfarin.
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