Publications by authors named "Francisco J Quintana"

168 Publications

The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation.

Proc Natl Acad Sci U S A 2021 May;118(19)

Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118;

Immune checkpoint inhibitors represent some of the most important cancer treatments developed in the last 20 y. However, existing immunotherapy approaches benefit only a minority of patients. Here, we provide evidence that the aryl hydrocarbon receptor (AhR) is a central player in the regulation of multiple immune checkpoints in oral squamous cell carcinoma (OSCC). Orthotopic transplant of mouse OSCC cells from which the AhR has been deleted (MOC1) results, within 1 wk, in the growth of small tumors that are then completely rejected within 2 wk, concomitant with an increase in activated T cells in tumor-draining lymph nodes (tdLNs) and T cell signaling within the tumor. By 2 wk, AhR control cells (MOC1), but not MOC1 cells up-regulate exhaustion pathways in the tumor-infiltrating T cells and expression of checkpoint molecules on CD4 T cells (PD-1, CTLA4, Lag3, and CD39) and macrophages, dendritic cells, and Ly6G myeloid cells (PD-L1 and CD39) in tdLNs. Notably, MOC1 cell transplant renders mice 100% immune to later challenge with wild-type tumors. Analysis of altered signaling pathways within MOC1 cells shows that the AhR controls baseline and IFNγ-induced and PD-L1 expression, the latter of which occurs through direct transcriptional control. These observations 1) confirm the importance of malignant cell AhR in suppression of tumor immunity, 2) demonstrate the involvement of the AhR in IFNγ control of PD-L1 and IDO expression in the cancer context, and 3) suggest that the AhR is a viable target for modulation of multiple immune checkpoints.
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http://dx.doi.org/10.1073/pnas.2012692118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126867PMC
May 2021

Barcoded viral tracing of single-cell interactions in central nervous system inflammation.

Science 2021 04;372(6540)

Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.

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.
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http://dx.doi.org/10.1126/science.abf1230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157482PMC
April 2021

Treatment of chronic diabetic foot ulcers with adipose-derived stromal vascular fraction cell injections: Safety and evidence of efficacy at 1 year.

Stem Cells Transl Med 2021 Apr 7. Epub 2021 Apr 7.

Diabetes Research Institute and Cellular Transplant Center, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA.

Diabetes affects multiple systems in complex manners. Diabetic foot ulcers (DFUs) are a result of diabetes-induced microarterial vessel disease and peripheral neuropathy. The presence of arteriosclerosis-induced macroarterial disease can further complicate DFU pathophysiology. Recent studies suggest that mesenchymal stromal cell therapies can enhance tissue regeneration. This phase I study was designed to determine the safety and explore the efficacy of local injections of autologous adipose-derived stromal vascular fraction (SVF) cells to treat nonhealing DFUs greater than 3 cm in diameter. Sixty-three patients with type 2 diabetes with chronic DFU-all amputation candidates-were treated with 30 × 10 SVF cells injected in the ulcer bed and periphery and along the pedal arteries. Patients were seen at 6 and 12 months to evaluate ulcer closure. Doppler ultrasounds were performed in a subset of subjects to determine vascular structural parameters. No intervention-related serious adverse events were reported. At 6 months, 51 subjects had 100% DFU closure, and 8 subjects had ≥75% closure. Three subjects had early amputations, and one subject died. At 12 months, 50 subjects had 100% DFU healing and 4 subjects had ≥85% healing. Five subjects died between the 6- and 12-month follow-up visits. No deaths were intervention related. Doppler studies in 11 subjects revealed increases in peak systolic velocity and pulsatility index in 33 of 33 arteries, consistent with enhanced distal arterial runoff. These results indicate that SVF can be safely used to treat chronic DFU, with evidence of efficacy (wound healing) and mechanisms of action that include vascular repair and/or angiogenesis.
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http://dx.doi.org/10.1002/sctm.20-0497DOI Listing
April 2021

Protein design-scapes generated by microfluidic DNA assembly elucidate domain coupling in the bacterial histidine kinase CpxA.

Proc Natl Acad Sci U S A 2021 Mar;118(12)

Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158;

The randomization and screening of combinatorial DNA libraries is a powerful technique for understanding sequence-function relationships and optimizing biosynthetic pathways. Although it can be difficult to predict a priori which sequence combinations encode functional units, it is often possible to omit undesired combinations that inflate library size and screening effort. However, defined library generation is difficult when a complex scan through sequence space is needed. To overcome this challenge, we designed a hybrid valve- and droplet-based microfluidic system that deterministically assembles DNA parts in picoliter droplets, reducing reagent consumption and bias. Using this system, we built a combinatorial library encoding an engineered histidine kinase (HK) based on bacterial CpxA. Our library encodes designed transmembrane (TM) domains that modulate the activity of the cytoplasmic domain of CpxA and variants of the structurally distant "S helix" located near the catalytic domain. We find that the S helix sets a basal activity further modulated by the TM domain. Surprisingly, we also find that a given TM motif can elicit opposing effects on the catalytic activity of different S-helix variants. We conclude that the intervening HAMP domain passively transmits signals and shapes the signaling response depending on subtle changes in neighboring domains. This flexibility engenders a richness in functional outputs as HKs vary in response to changing evolutionary pressures.
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http://dx.doi.org/10.1073/pnas.2017719118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000134PMC
March 2021

Therapeutic induction of tolerogenic dendritic cells via aryl hydrocarbon receptor signaling.

Curr Opin Immunol 2021 Feb 16;70:33-39. Epub 2021 Feb 16.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.coi.2021.02.003DOI Listing
February 2021

Reactive astrocyte nomenclature, definitions, and future directions.

Nat Neurosci 2021 03 15;24(3):312-325. Epub 2021 Feb 15.

Dpto. Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
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http://dx.doi.org/10.1038/s41593-020-00783-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007081PMC
March 2021

Microglia and Central Nervous System-Associated Macrophages-From Origin to Disease Modulation.

Annu Rev Immunol 2021 04 8;39:251-277. Epub 2021 Feb 8.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; email:

The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.
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http://dx.doi.org/10.1146/annurev-immunol-093019-110159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085109PMC
April 2021

Gut-licensed IFNγ NK cells drive LAMP1TRAIL anti-inflammatory astrocytes.

Nature 2021 Feb 6;590(7846):473-479. Epub 2021 Jan 6.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions. However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR-Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP1 and the death receptor ligand TRAIL. LAMP1TRAIL astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL-DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1TRAIL astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ NK cells that are licensed by the microbiome.
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http://dx.doi.org/10.1038/s41586-020-03116-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039910PMC
February 2021

The aryl hydrocarbon receptor and the gut-brain axis.

Cell Mol Immunol 2021 Feb 6;18(2):259-268. Epub 2021 Jan 6.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified as the receptor for dioxin. Almost half a century after its discovery, AHR is now recognized as a receptor for multiple physiological ligands, with important roles in health and disease. In this review, we discuss the role of AHR in the gut-brain axis and its potential value as a therapeutic target for immune-mediated diseases.
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http://dx.doi.org/10.1038/s41423-020-00585-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027889PMC
February 2021

Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS.

Neurol Neuroimmunol Neuroinflamm 2021 03 6;8(2). Epub 2021 Jan 6.

From the Ann Romney Center for Neurologic Diseases (V.R., J.E.K., Z.L., E.T., M.C.T., C.-C.C., K.A.d.L., D.M.B., F.J.Q.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Klinikum rechts der Isar (V.R.), Department of Neurology, Technical University of Munich, Germany; Department of Neurology (V.R.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany; Ayala Pharmaceuticals (J.K.), Rehovot, Israel; and Broad Institute of MIT and Harvard (F.J.Q.), Cambridge, MA.

Objective: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS.

Methods: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes.

Results: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia.

Conclusions: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.
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http://dx.doi.org/10.1212/NXI.0000000000000946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862099PMC
March 2021

A cell-based drug delivery platform for treating central nervous system inflammation.

J Mol Med (Berl) 2021 May 4;99(5):663-671. Epub 2021 Jan 4.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA, USA.

Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4 T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases. KEY MESSAGES: MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425. Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells. Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425. Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.
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http://dx.doi.org/10.1007/s00109-020-02003-9DOI Listing
May 2021

Aryl Hydrocarbon Receptor Plasma Agonist Activity Correlates With Disease Activity in Progressive MS.

Neurol Neuroimmunol Neuroinflamm 2021 03 24;8(2). Epub 2020 Dec 24.

From the Department of Neurology (T.T., T.B., L.N., M.L., V.G., M.B., M.M., T.K., B.H., V.R.), Klinikum rechts der Isar, Technical University of Munich; Department of Neurology (T.T., V.R.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuernberg; Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany; Ann Romney Center for Neurologic Diseases (E.T., F.J.Q.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard (F.J.Q.), Cambridge, MA; and TUM-Neuroimaging Center (M.B., M.M.), Klinikum rechts der Isar, Technische Universität München, Germany.

Objective: The relationship between serum aryl hydrocarbon receptor (AHR) agonistic activity levels with disease severity, its modulation over the course of relapsing-remitting MS (RRMS), and its regulation in progressive MS (PMS) are unknown. Here, we report the analysis of AHR agonistic activity levels in cross-sectional and longitudinal serum samples of patients with RRMS and PMS.

Methods: In a cross-sectional investigation, a total of 36 control patients diagnosed with noninflammatory diseases, 84 patients with RRMS, 35 patients with secondary progressive MS (SPMS), and 41 patients with primary progressive MS (PPMS) were included in this study. AHR activity was measured in a cell-based luciferase assay and correlated with age, sex, the presence of disease-modifying therapies, Expanded Disability Status Scale scores, and disease duration. In a second longitudinal investigation, we analyzed AHR activity in 13 patients diagnosed with RRMS over a period from 4 to 10 years and correlated AHR agonistic activity with white matter atrophy and lesion load volume changes.

Results: In RRMS, AHR ligand levels were globally decreased and associated with disease duration and neurologic disability. In SPMS and PPMS, serum AHR agonistic activity was decreased and correlated with disease severity. Finally, in longitudinal serum samples of patients with RRMS, decreased AHR agonistic activity was linked to progressive CNS atrophy and increased lesion load.

Conclusions: These findings suggest that serum AHR agonist levels negatively correlate with disability in RRMS and PMS and decrease longitudinally in correlation with MRI markers of disease progression. Thus, serum AHR agonistic activity may serve as novel biomarker for disability progression in MS.
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http://dx.doi.org/10.1212/NXI.0000000000000933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768947PMC
March 2021

SARS-CoV-2-induced lung pathology: AHR as a candidate therapeutic target.

Cell Res 2021 01;31(1):1-2

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

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http://dx.doi.org/10.1038/s41422-020-00447-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705403PMC
January 2021

Tolerogenic nanoparticles suppress central nervous system inflammation.

Proc Natl Acad Sci U S A 2020 12 25;117(50):32017-32028. Epub 2020 Nov 25.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115;

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) 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 MOG-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.
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http://dx.doi.org/10.1073/pnas.2016451117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749362PMC
December 2020

T Follicular Regulatory Cell-Derived Fibrinogen-like Protein 2 Regulates Production of Autoantibodies and Induction of Systemic Autoimmunity.

J Immunol 2020 12 9;205(12):3247-3262. Epub 2020 Nov 9.

Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

T follicular regulatory (TFR) cells limit Ab responses, but the underlying mechanisms remain largely unknown. In this study, we identify Fgl2 as a soluble TFR cell effector molecule through single-cell gene expression profiling. Highly expressed by TFR cells, Fgl2 directly binds to B cells, especially light-zone germinal center B cells, as well as to T follicular helper (TFH) cells, and directly regulates B cells and TFH in a context-dependent and type 2 Ab isotype-specific manner. In TFH cells, Fgl2 induces the expression of Prdm1 and a panel of checkpoint molecules, including PD1, TIM3, LAG3, and TIGIT, resulting in TFH cell dysfunction. Mice deficient in Fgl2 had dysregulated Ab responses at steady-state and upon immunization. In addition, loss of Fgl2 results in expansion of autoreactive B cells upon immunization. Consistent with this observation, aged Fgl2 mice spontaneously developed autoimmunity associated with elevated autoantibodies. Thus, Fgl2 is a TFR cell effector molecule that regulates humoral immunity and limits systemic autoimmunity.
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http://dx.doi.org/10.4049/jimmunol.2000748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725915PMC
December 2020

Editorial: Update on Translational Neuroimmunology - Research of ISNI 2018.

Front Immunol 2020 30;11:2012. Epub 2020 Sep 30.

Center for Neuroinflammation and Experimental Therapeutics & Multiple Sclerosis Division, Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States.

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http://dx.doi.org/10.3389/fimmu.2020.02012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554330PMC
May 2021

Targeted Single-Cell RNA and DNA Sequencing With Fluorescence-Activated Droplet Merger.

Anal Chem 2020 11 13;92(21):14616-14623. Epub 2020 Oct 13.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94158, United States.

Analyzing every cell in a diverse sample provides insight into population-level heterogeneity, but abundant cell types dominate the analysis and rarer populations are scarcely represented in the data. To focus on specific cell types, the current paradigm is to physically isolate subsets of interest prior to analysis; however, it remains difficult to isolate and then single-cell sequence such populations because of compounding losses. Here, we describe an alternative approach that selectively merges cells with reagents to achieve enzymatic reactions without having to physically isolate cells. We apply this technique to perform single-cell transcriptome and genome sequencing of specific cell subsets. Our method for analyzing heterogeneous populations obviates the need for pre- or post-enrichment and simplifies single-cell workflows, making it useful for other applications in single-cell biology, combinatorial chemical synthesis, and drug screening.
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http://dx.doi.org/10.1021/acs.analchem.0c03059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182774PMC
November 2020

Negative feedback control of neuronal activity by microglia.

Nature 2020 10 30;586(7829):417-423. Epub 2020 Sep 30.

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor AR are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.
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http://dx.doi.org/10.1038/s41586-020-2777-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577179PMC
October 2020

Astrocyte Crosstalk in CNS Inflammation.

Neuron 2020 11 7;108(4):608-622. Epub 2020 Sep 7.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated with specific genomic programs and functions. The advent of novel genomic technologies has enabled rapid progress in the characterization of astrocyte heterogeneity and its control by astrocyte interactions with other cells in the central nervous system (CNS). In this review, we provide an overview of the multifaceted roles of astrocytes in the context of CNS inflammation, highlighting recent discoveries on astrocyte subsets and their regulation. We explore mechanisms of crosstalk between astrocytes and other cells in the CNS in the context of neuroinflammation and neurodegeneration and discuss how these interactions shape pathological outcomes.
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http://dx.doi.org/10.1016/j.neuron.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704785PMC
November 2020

The Role of Astrocytes in CNS Inflammation.

Trends Immunol 2020 09 13;41(9):805-819. Epub 2020 Aug 13.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Astrocytes are the most abundant cell type in the central nervous system (CNS), performing complex functions in health and disease. It is now clear that multiple astrocyte subsets or activation states (plastic phenotypes driven by intrinsic and extrinsic cues) can be identified, associated to specific genomic programs and functions. The characterization of these subsets and the mechanisms that control them may provide unique insights into the pathogenesis of neurologic diseases, and identify potential targets for therapeutic intervention. In this article, we provide an overview of the role of astrocytes in CNS inflammation, highlighting recent discoveries on astrocyte subsets and the mechanisms that control them.
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http://dx.doi.org/10.1016/j.it.2020.07.007DOI Listing
September 2020

A potential role for AHR in SARS-CoV-2 pathology.

Res Sq 2020 Apr 27. Epub 2020 Apr 27.

Broad Institute of MIT and Harvard.

Coronavirus infection is associated to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists decrease viral titers and ameliorate ZIKV-induced pathology . Here we report that AHR is activated during coronavirus infection, impacting anti-viral immunity and lung basal cells associated to tissue repair. Hence, AHR antagonists are candidate therapeutics for the management of coronavirus-infected patients.
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http://dx.doi.org/10.21203/rs.3.rs-25639/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336521PMC
April 2020

AHR is a Zika virus host factor and a candidate target for antiviral therapy.

Nat Neurosci 2020 08 20;23(8):939-951. Epub 2020 Jul 20.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine (Kyn) production, which activates AHR, limiting the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia (PML) protein, which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro and also suppressed replication of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication and PML protein as a driver of anti-ZIKV intrinsic immunity.
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http://dx.doi.org/10.1038/s41593-020-0664-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897397PMC
August 2020

Checkpoint Receptor TIGIT Expressed on Tim-1 B Cells Regulates Tissue Inflammation.

Cell Rep 2020 07;32(2):107892

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address:

Tim-1, a phosphatidylserine receptor expressed on B cells, induces interleukin 10 (IL-10) production by sensing apoptotic cells. Here we show that mice with B cell-specific Tim-1 deletion develop tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Transcriptomic analysis demonstrates that besides IL-10, Tim-1 B cells also differentially express a number of co-inhibitory checkpoint receptors including TIGIT. Mice with B cell-specific TIGIT deletion develop spontaneous paralysis with CNS inflammation, but with limited inflammation in other organs. Our findings suggest that Tim-1 B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 signaling-dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. A possible critical role of aryl hydrocarbon receptor (AhR) in regulating the B cell function is discussed, as we find that AhR is among the preferentially expressed transcription factors in Tim-1 B cells and regulates their TIGIT and IL-10 expression.
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http://dx.doi.org/10.1016/j.celrep.2020.107892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496220PMC
July 2020

The Gut-CNS Axis in Multiple Sclerosis.

Trends Neurosci 2020 08 7;43(8):622-634. Epub 2020 Jul 7.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Electronic address:

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS driven by the inflammatory activity of peripheral immune cells recruited to the CNS and by CNS-resident glial cells. MS pathogenesis has been linked to both genetic and environmental factors. In addition, the commensal flora have been shown to modulate immune processes relevant to MS pathogenesis. We discuss the effects of the gut microbiota on T cells and glial cells, and their relevance for the control of inflammation and neurodegeneration in MS. A better understanding of the gut-CNS axis will shed new light on the mechanisms of disease pathogenesis, and may help to guide the development of efficacious therapies for MS.
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http://dx.doi.org/10.1016/j.tins.2020.06.002DOI Listing
August 2020

DNA vaccine encoding heat shock protein 90 protects from murine lupus.

Arthritis Res Ther 2020 06 22;22(1):152. Epub 2020 Jun 22.

Department of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies to multiple self-antigens, including heat shock proteins (HSP). Because of the increased expression of HSP90 and abnormal immune responses to it in SLE, we investigated whether an HSP90 DNA vaccine could modulate the development and clinical manifestations of SLE in lupus-prone mice.

Methods: (NZB x NZW)F (NZB/W) mice were vaccinated with DNA constructs encoding HSP90 or control plasmids or vehicle. The mice were then monitored for survival, circulating anti-dsDNA autoantibodies, and immune phenotypes. Renal disease was evaluated by immunohistochemistry and by the measurement of proteinuria.

Results: Vaccination with HSP90 DNA reduced lupus disease manifestations and prolonged the survival of NZB/W mice. The protective effects of the HSP90 DNA vaccine associated with the induction of tolerogenic dendritic cells (DCs) and an expansion of T regulatory cells (Tregs).

Conclusions: The beneficial effects of DNA vaccination with HSP90 in murine SLE support the possibility of HSP90-based therapeutic modalities of intervention in SLE.
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http://dx.doi.org/10.1186/s13075-020-02246-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310240PMC
June 2020

Serum antibodies to phosphatidylcholine in MS.

Neurol Neuroimmunol Neuroinflamm 2020 07 9;7(4). Epub 2020 Jun 9.

From the Ann Romney Center for Neurologic Diseases (M.C.S., V.R., P.K., R.B., H.L.W., F.J.Q.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Facultad de Medicina (M.C.S., U.M., C.S., E.E.), Instituto de Medicina Molecular Aplicada (INMA), Universidad San Pablo-CEU, CEU Universities, Madrid; Molecular Biology Service and MS Unit (M.I.G.S., G.I.), University of Sevilla; Department of Neurology (S.L.H., S.E.B., J.R.O.), University of California, San Francisco; Instituto de Investigación Sanitaria San Carlos (IdISSC) (R.Á.-L.), Hospital Clínico San Carlos, Madrid, Spain; and The Broad Institute of Harvard and MIT (F.J.Q.), Cambridge, MA.

Objective: To evaluate the value of serum immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies reactive with phosphatidylcholine (PC) and lactosylceramide (LC) as biomarkers in MS.

Methods: We developed an ultrasensitive ELISA technique to analyze serum IgG and IgM antibodies to LC and PC, which we used to analyze samples from 362 patients with MS, 10 patients with non-MS myelin diseases (Non-MSMYDs), 11 patients with nonmyelin neurologic diseases (Non-MYNDs), and 80 controls. MS serum samples included clinically isolated syndrome (CIS, n = 17), relapsing-remitting MS (RRMS, n = 62), secondary progressive MS (SPMS, n = 50), primary progressive MS (PPMS, n = 37), and benign MS (BENMS, n = 36).

Results: We detected higher levels of serum IgM antibodies to PC (IgM-PC) in MS than control samples; patients with CIS and RRMS showed higher IgM-PC levels than patients with SPMS, PPMS, and BENMS and controls. MS and control samples did not differ in serum levels of IgM antibodies reactive with LC, nor in IgG antibodies reactive with LC or PC.

Conclusions: Serum IgM-PC antibodies are elevated in patients with MS, particularly during the CIS and RRMS phases of the disease. Thus, serum IgM-PC is a candidate biomarker for early inflammatory stages of MS.

Classification Of Evidence: This study provides Class III evidence that serum antibodies to PC are elevated in patients with MS. The study is rated Class III because of the case control design and the risk of spectrum bias: antibody levels in patients with MS were compared with healthy controls.
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http://dx.doi.org/10.1212/NXI.0000000000000765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309529PMC
July 2020

The NLRP3 inflammasome in progressive multiple sclerosis.

Brain 2020 05;143(5):1286-1288

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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http://dx.doi.org/10.1093/brain/awaa135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241945PMC
May 2020

Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α-dependent pathways.

Proc Natl Acad Sci U S A 2020 06 14;117(22):12269-12280. Epub 2020 May 14.

Cellular Immunology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;

In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on and (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.
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http://dx.doi.org/10.1073/pnas.1918196117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275751PMC
June 2020

Role of sphingolipid metabolism in neurodegeneration.

J Neurochem 2020 May 13. Epub 2020 May 13.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.

Sphingolipids are a class of lipids highly enriched in the central nervous system (CNS), which shows great diversity and complexity, and has been implicated in CNS development and function. Alterations in sphingolipid metabolism have been described in multiple diseases, including those affecting the central nervous system (CNS). In this review, we discuss the role of sphingolipid metabolism in neurodegeneration, evaluating its direct roles in neuron development and health, and also in the induction of neurotoxic activities in CNS-resident astrocytes and microglia in the context of neurologic diseases such as multiple sclerosis and Alzheimer's disease. Finally, we focus on the metabolism of gangliosides and sphingosine-1-phosphate, its contribution to the pathogenesis of neurologic diseases, and its potential as a candidate target for the therapeutic modulation of neurodegeneration.
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http://dx.doi.org/10.1111/jnc.15044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665988PMC
May 2020