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1.
Nature ; 620(7975): 881-889, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37558878

ABSTRACT

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, 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.


Subject(s)
Autoimmune Diseases , Central Nervous System , Dendritic Cells , Hypoxia-Inducible Factor 1, alpha Subunit , Lactic Acid , Humans , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Autoimmune Diseases/prevention & control , Autoimmunity , Central Nervous System/cytology , Central Nervous System/immunology , Central Nervous System/pathology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/chemistry , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lactic Acid/metabolism , Probiotics/therapeutic use , Reactive Oxygen Species/metabolism , T-Lymphocytes/immunology , Feedback, Physiological , Lactase/genetics , Lactase/metabolism , Single-Cell Analysis
2.
bioRxiv ; 2023 Mar 21.
Article in English | MEDLINE | ID: mdl-36993446

ABSTRACT

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

3.
Nature ; 611(7937): 801-809, 2022 11.
Article in English | MEDLINE | ID: mdl-36266581

ABSTRACT

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPß signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.


Subject(s)
Environment , Herbicides , Inflammation , Inflammatory Bowel Diseases , Intestines , Animals , Mice , Inflammation/chemically induced , Inflammation/etiology , Inflammation/immunology , Inflammation/pathology , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Zebrafish , Machine Learning , Databases, Factual , Disease Models, Animal , Intestines/drug effects , Intestines/immunology , Intestines/metabolism , Intestines/pathology , NF-kappa B , CCAAT-Enhancer-Binding Protein-beta , Receptors, Aryl Hydrocarbon , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/metabolism , Herbicides/adverse effects
4.
iScience ; 25(9): 105004, 2022 Sep 16.
Article in English | MEDLINE | ID: mdl-36093065

ABSTRACT

Glucose, the critical energy source in the human body, is considered a potential risk factor in various autoimmune diseases when consumed in high amounts. However, the roles of glucose at moderate doses in the regulation of autoimmune inflammatory diseases and CD4+ T cell responses are controversial. Here, we show that while glucose at a high concentration (20% w/v) promotes intestinal inflammation, it suppresses colitis at a moderate dose (6% w/v), which increases the proportion of intestinal regulatory T (Treg) cells but does not affect effector CD4+ T cells. Glucose treatment promotes Treg cell differentiation but it does not affect Treg stability. Feeding glucose alters gut microbiota compositions, which are not involved in the glucose induction of Treg cells. Glucose promotes aryl hydrocarbon receptor (AhR) activation to induce Treg polarization. These findings reveal the different effects of glucose at different doses on the intestinal immune response.

5.
Nat Med ; 27(7): 1212-1222, 2021 07.
Article in English | MEDLINE | ID: mdl-34183837

ABSTRACT

Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies.


Subject(s)
Adenosine Triphosphate/metabolism , Apyrase/metabolism , Inflammatory Bowel Diseases/therapy , Probiotics/therapeutic use , Receptors, Purinergic P2Y2/metabolism , Saccharomyces cerevisiae/metabolism , Animals , Apyrase/genetics , CRISPR-Cas Systems/genetics , Disease Models, Animal , Dysbiosis/prevention & control , Female , Fibrosis/prevention & control , Gastrointestinal Microbiome/physiology , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/pathology , Humans , Inflammatory Bowel Diseases/pathology , Male , Mice , Mice, Inbred C57BL , Receptors, Purinergic P2Y2/genetics , Saccharomyces cerevisiae/genetics
6.
Science ; 372(6540)2021 04 23.
Article in English | MEDLINE | ID: mdl-33888612

ABSTRACT

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.


Subject(s)
Astrocytes/physiology , Cell Communication , Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Microglia/physiology , Multiple Sclerosis/physiopathology , Single-Cell Analysis , Animals , Antigens, CD/metabolism , Brain/pathology , Brain/physiopathology , Central Nervous System/physiopathology , Encephalomyelitis, Autoimmune, Experimental/pathology , Ephrin-B3/metabolism , Herpesvirus 1, Suid/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Multiple Sclerosis/pathology , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , RNA-Seq , Reactive Oxygen Species/metabolism , Receptor, EphB3/antagonists & inhibitors , Receptor, EphB3/metabolism , Receptors, Cell Surface/metabolism , Semaphorins/metabolism , Signal Transduction , T-Lymphocytes/physiology , TOR Serine-Threonine Kinases/metabolism
7.
Proc Natl Acad Sci U S A ; 117(50): 32017-32028, 2020 12 15.
Article in English | MEDLINE | ID: mdl-33239445

ABSTRACT

Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for the treatment of autoimmune diseases, including multiple sclerosis (MS). Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is a candidate target for novel immunotherapies. Here, we report the development of AhR-activating nanoliposomes (NLPs) to induce antigen-specific tolerance. NLPs loaded with the AhR agonist ITE and a T cell epitope from myelin oligodendrocyte glycoprotein (MOG)35-55 induced tolerogenic dendritic cells and suppressed the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, in preventive and therapeutic setups. EAE suppression was associated with the expansion of MOG35-55-specific FoxP3+ regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concomitant with a reduction in central nervous system-infiltrating effector T cells (Teff cells). Notably, NLPs induced bystander suppression in the EAE model established in C57BL/6 × SJL F1 mice. Moreover, NLPs ameliorated chronic progressive EAE in nonobese diabetic mice, a model which resembles some aspects of secondary progressive MS. In summary, these studies describe a platform for the therapeutic induction of antigen-specific tolerance in autoimmune diseases.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Immune Tolerance/drug effects , Immunosuppressive Agents/administration & dosage , Multiple Sclerosis/drug therapy , Animals , Bystander Effect/drug effects , Bystander Effect/immunology , Drug Combinations , Encephalomyelitis, Autoimmune, Experimental/immunology , Epitopes, T-Lymphocyte/immunology , Female , Humans , Immunosuppressive Agents/immunology , Indoles/administration & dosage , Indoles/immunology , Liposomes , Mice , Multiple Sclerosis/immunology , Myelin-Oligodendrocyte Glycoprotein/administration & dosage , Myelin-Oligodendrocyte Glycoprotein/immunology , Nanoparticles/chemistry , Peptide Fragments/administration & dosage , Peptide Fragments/immunology , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , Thiazoles/administration & dosage , Thiazoles/immunology
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