RESUMEN
Phagocytic microglia such as proliferative region-associated microglia and disease-associated microglia appear in the brain transiently during development and across various brain pathologies, but their function and degree of plasticity remain unclear. In this issue of Immunity, Barclay et al. established a novel Clec7a-CreERT2 mouse line to uncover the plasticity of this cell state and its role in a model of myelin injury.
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Plasticidad de la Célula , Microglía , Fagocitosis , Microglía/inmunología , Microglía/fisiología , Animales , Ratones , Plasticidad de la Célula/inmunología , Vaina de Mielina/inmunología , Vaina de Mielina/metabolismo , Humanos , Encéfalo/inmunologíaRESUMEN
Tissue aging can be viewed as a loss of normal maintenance; in advanced age, the mechanisms which keep the tissue healthy on daily bases fail to manage the accumulating "wear and tear", leading to gradual loss of function. In the brain, maintenance is provided primarily by three components: the blood-brain barrier, which allows the influx of certain molecules into the brain while excluding others, the circulation of the cerebrospinal fluid, and the phagocytic function of microglia. Indeed, failure of these systems is associated with cognitive loss and other hallmarks of brain aging. Interestingly, all three mechanisms are regulated not only by internal conditions within the aging brain, but remain highly sensitive to the peripheral signals, such as cytokines or microbiome-derived molecules, present in the systemic circulation. In this article, we discuss the contribution of such peripheral factors to brain maintenance and its loss in aging.
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Encéfalo , Microglía , Citocinas , Factores Inmunológicos , Microglía/fisiologíaRESUMEN
Despite their key regulatory role and therapeutic potency, the molecular signatures of interactions between T cells and antigen-presenting myeloid cells within the tumor microenvironment remain poorly characterized. Here, we systematically characterize these interactions using RNA sequencing of physically interacting cells (PIC-seq) and find that CD4+PD-1+CXCL13+ T cells are a major interacting hub with antigen-presenting cells in the tumor microenvironment of human non-small cell lung carcinoma. We define this clonally expanded, tumor-specific and conserved T-cell subset as T-helper tumor (Tht) cells. Reconstitution of Tht cells in vitro and in an ovalbumin-specific αß TCR CD4+ T-cell mouse model, shows that the Tht program is primed in tumor-draining lymph nodes by dendritic cells presenting tumor antigens, and that their function is important for harnessing the antitumor response of anti-PD-1 treatment. Our molecular and functional findings support the modulation of Tht-dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy.
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Neoplasias Pulmonares , Microambiente Tumoral , Animales , Línea Celular Tumoral , Células Dendríticas , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/terapia , Ratones , Linfocitos T Colaboradores-InductoresRESUMEN
The brain is no longer considered as an organ functioning in isolation; accumulating evidence suggests that changes in the peripheral immune system can indirectly shape brain function. At the interface between the brain and the systemic circulation, the choroid plexuses (CP), which constitute the blood-cerebrospinal fluid barrier, have been highlighted as a key site of periphery-to-brain communication. CP produce the cerebrospinal fluid, neurotrophic factors, and signaling molecules that can shape brain homeostasis. CP are also an active immunological niche. In contrast to the brain parenchyma, which is populated mainly by microglia under physiological conditions, the heterogeneity of CP immune cells recapitulates the diversity found in other peripheral organs. The CP immune cell diversity and activity change with aging, stress, and disease and modulate the activity of the CP epithelium, thereby indirectly shaping brain function. The goal of this protocol is to isolate murine CP and identify about 90% of the main immune subsets that populate them. This method is a tool to characterize CP immune cells and understand their function in orchestrating periphery-to-brain communication. The proposed protocol may help decipher how CP immune cells indirectly modulate brain function in health and across various disease conditions.
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Barrera Hematoencefálica , Plexo Coroideo , Envejecimiento , Animales , Barrera Hematoencefálica/fisiología , Encéfalo/fisiología , Coroides , RatonesRESUMEN
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.
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Células Dendríticas/inmunología , Hígado Graso/inmunología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Receptores de Quimiocina/genética , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Reprogramación Celular/genética , Reprogramación Celular/inmunología , Células Dendríticas/patología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Hígado Graso/genética , Hígado Graso/patología , Femenino , Humanos , Hígado/inmunología , Hígado/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Receptores de Quimiocina/inmunología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
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Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Inmunoterapia , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/inmunología , Animales , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinogénesis/inmunología , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/inmunología , Progresión de la Enfermedad , Humanos , Hígado/inmunología , Hígado/patología , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Tertiary lymphoid structures (TLS) are organized aggregates of B and T cells formed ectopically during different stages of life in response to inflammation, infection, or cancer. Here, we describe formation of structures reminiscent of TLS in the spinal cord meninges under several central nervous system (CNS) pathologies. After acute spinal cord injury, B and T lymphocytes locally aggregate within the meninges to form TLS-like structures, and continue to accumulate during the late phase of the response to the injury, with a negative impact on subsequent pathological conditions, such as experimental autoimmune encephalomyelitis. Using a chronic model of spinal cord pathology, the mSOD1 mouse model of amyotrophic lateral sclerosis, we further showed by single-cell RNA-sequencing that a meningeal lymphocyte niche forms, with a unique organization and activation state, including accumulation of pre-B cells in the spinal cord meninges. Such a response was not found in the CNS-draining cervical lymph nodes. The present findings suggest that a special immune response develops in the meninges during various neurological pathologies in the CNS, a possible reflection of its immune privileged nature.
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Esclerosis Amiotrófica Lateral/inmunología , Linfocitos B/inmunología , Inmunidad , Meninges/inmunología , Traumatismos de la Médula Espinal/inmunología , Linfocitos T/inmunología , Estructuras Linfoides Terciarias/inmunología , Enfermedad Aguda , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Inflamación/inmunología , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Cuello , Vértebras Torácicas/lesionesRESUMEN
Alzheimer's disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling.
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Glicoproteínas de Membrana/metabolismo , Transducción de Señal/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Humanos , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Viruses are a constant threat to global health as highlighted by the current COVID-19 pandemic. Currently, lack of data underlying how the human host interacts with viruses, including the SARS-CoV-2 virus, limits effective therapeutic intervention. We introduce Viral-Track, a computational method that globally scans unmapped single-cell RNA sequencing (scRNA-seq) data for the presence of viral RNA, enabling transcriptional cell sorting of infected versus bystander cells. We demonstrate the sensitivity and specificity of Viral-Track to systematically detect viruses from multiple models of infection, including hepatitis B virus, in an unsupervised manner. Applying Viral-Track to bronchoalveloar-lavage samples from severe and mild COVID-19 patients reveals a dramatic impact of the virus on the immune system of severe patients compared to mild cases. Viral-Track detects an unexpected co-infection of the human metapneumovirus, present mainly in monocytes perturbed in type-I interferon (IFN)-signaling. Viral-Track provides a robust technology for dissecting the mechanisms of viral-infection and pathology.
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Infecciones por Coronavirus/fisiopatología , Interacciones Huésped-Patógeno , Neumonía Viral/fisiopatología , Programas Informáticos , Animales , Betacoronavirus/aislamiento & purificación , COVID-19 , Coinfección/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Humanos , Interferones/inmunología , Pulmón/patología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/patología , Neumonía Viral/virología , SARS-CoV-2 , Sensibilidad y Especificidad , Análisis de Secuencia de ARN , Índice de Severidad de la Enfermedad , Análisis de la Célula IndividualRESUMEN
Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.
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Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Dieta Alta en Grasa , Intolerancia a la Glucosa , Humanos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Metabolismo de los Lípidos/genética , Lípidos/análisis , Macrófagos/citología , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , Monocitos/metabolismo , Obesidad/metabolismo , Obesidad/patología , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Transducción de Señal , Análisis de la Célula IndividualRESUMEN
Immune cells patrol the brain and can support its function, but can we modulate brain-immune communication to fight neurological diseases? Here, we briefly discuss the mechanisms orchestrating the cross-talk between the brain and the immune system and describe how targeting this interaction in a well-controlled manner could be developed as a universal therapeutic approach to treat neurodegeneration.
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Encéfalo/inmunología , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/terapia , Animales , Encéfalo/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Enfermedades Neurodegenerativas/patologíaRESUMEN
In the version of this article initially published, the annotation accompanying ref. 47 ended with "though the modulation of microglia." The first word of this phrase should have been "through." The error has been corrected in the HTML and PDF versions of the article.
RESUMEN
A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body's intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities.
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Microglía/metabolismo , Enfermedades Neurodegenerativas/patología , Animales , Sistema Nervioso Central/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/metabolismo , Receptores Inmunológicos/metabolismo , Transducción de SeñalRESUMEN
Microglia differentiate from progenitors that infiltrate the nascent CNS during early embryonic development. They then remain in this unique immune-privileged environment throughout life. Multiple immune mechanisms, which we collectively refer to as microglial checkpoints, ensure efficient and tightly regulated microglial responses to perturbations in the CNS milieu. Such mechanisms are essential for proper CNS development and optimal physiological function. However, in chronic disease or aging, when a robust immune response is required, such checkpoint mechanisms may limit the ability of microglia to protect the CNS. Here we survey microglial checkpoint mechanisms and their roles in controlling microglial function throughout life and in disease, and discuss how they may be targeted therapeutically.
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Activación de Macrófagos/fisiología , Microglía/inmunología , Envejecimiento/inmunología , Envejecimiento/patología , Animales , Humanos , Microglía/patología , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/patología , Linfocitos T/inmunologíaRESUMEN
During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-ß in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.Microglia cells in the brain regulate immune responses, but in ageing can negatively affect brain function. Here the authors show that the chronic presence of type I interferon in aged mouse brain impedes cognitive ability by altering microglia transcriptome and limiting Mef2C, a microglia 'off' signal.
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Envejecimiento/inmunología , Encéfalo/inmunología , Interferón beta/inmunología , Factores de Transcripción MEF2/inmunología , Microglía/inmunología , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Humanos , Interferón beta/genética , Factores de Transcripción MEF2/genética , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Neuroinflammation is common to various diseases of the central nervous system (CNS), but its imprecise definition has led to many misconceptions in research and clinical approaches. It is now recognized that neuroinflammation in chronic neurodegenerative conditions, including Alzheimer's disease (AD) and age-related dementia, is distinct from the inflammation that accompanies relapsing-remitting multiple sclerosis (RRMS), and its experimental animal model, experimental autoimmune encephalomyelitis (EAE). Here, we discuss the discrete features of inflammation in different CNS pathologies, given the current understanding of the CNS-immune crosstalk; the roles of the immune cells that are involved, their phenotypes, and their location and route of entry to the CNS. Understanding the term neuroinflammation to encompass a broad range of disease-specific conditions is essential for finding effective therapeutic approaches for these pathologies.
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Enfermedad de Alzheimer/inmunología , Encéfalo/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Sistema Inmunológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Inflamación Neurogénica , Neuroinmunomodulación , Animales , Modelos Animales de Enfermedad , Humanos , Interferones/metabolismo , RatonesRESUMEN
Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.