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Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Dexametasona , Monocitos , SARS-CoV-2 , Análisis de la Célula Individual , Humanos , Dexametasona/farmacología , Dexametasona/uso terapéutico , Monocitos/metabolismo , Monocitos/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Masculino , Femenino , Transcriptoma , Persona de Mediana Edad , Anciano , Glucocorticoides/uso terapéutico , Glucocorticoides/farmacología , Pulmón/patología , AdultoRESUMEN
Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.
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Proteína 1 Similar al Receptor de Interleucina-1 , Linfocitos T Reguladores , Femenino , Masculino , Humanos , Grasa Intraabdominal , Citocinas , Inflamación , GlucosaRESUMEN
The immune system is highly complex and distributed throughout an organism, with hundreds to thousands of cell states existing in parallel with diverse molecular pathways interacting in a highly dynamic and coordinated fashion. Although the characterization of individual genes and molecules is of the utmost importance for understanding immune-system function, high-throughput, high-resolution omics technologies combined with sophisticated computational modeling and machine-learning approaches are creating opportunities to complement standard immunological methods with new insights into immune-system dynamics. Like systems immunology itself, immunology researchers must take advantage of these technologies and form their own diverse networks, connecting with researchers from other disciplines. This Review is an introduction and 'how-to guide' for immunologists with no particular experience in the field of omics but with the intention to learn about and apply these systems-level approaches, and for immunologists who want to make the most of interdisciplinary networks.
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Sistema Inmunológico , Aprendizaje Automático , Simulación por ComputadorRESUMEN
Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections.
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Candida albicans/inmunología , Candidiasis/inmunología , Infecciones por Escherichia coli/inmunología , Escherichia coli/inmunología , Herencia , Inmunidad Innata/genética , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Células Mieloides/inmunología , Animales , Candida albicans/patogenicidad , Candidiasis/genética , Candidiasis/metabolismo , Candidiasis/microbiología , Células Cultivadas , Metilación de ADN , Modelos Animales de Enfermedad , Epigénesis Genética , Escherichia coli/patogenicidad , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Interacciones Huésped-Patógeno , Listeria monocytogenes/patogenicidad , Listeriosis/genética , Listeriosis/metabolismo , Listeriosis/microbiología , Masculino , Ratones Transgénicos , Células Mieloides/metabolismo , Células Mieloides/microbiología , Espermatozoides/inmunología , Espermatozoides/metabolismo , Transcripción GenéticaRESUMEN
Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of ß-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1ß and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.
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Inmunidad Innata , Memoria Inmunológica , Células Progenitoras Mieloides/inmunología , Animales , Células Cultivadas , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células Progenitoras Mieloides/efectos de los fármacos , Mielopoyesis/inmunología , beta-Glucanos/farmacologíaRESUMEN
Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.
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Vida Libre de Gérmenes , Microbiota , Microglía/citología , Efectos Tardíos de la Exposición Prenatal/microbiología , Transcriptoma , Animales , Encéfalo/citología , Encéfalo/embriología , Encéfalo/metabolismo , Diferenciación Celular , Células Cultivadas , Ensamble y Desensamble de Cromatina , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Embarazo , Factores SexualesRESUMEN
Regulatory T (Treg) cells accumulate into tumors, hindering the success of cancer immunotherapy. Yet, therapeutic targeting of Treg cells shows limited efficacy or leads to autoimmunity. The molecular mechanisms that guide Treg cell stability in tumors remain elusive. In the present study, we identify a cell-intrinsic role of the alarmin interleukin (IL)-33 in the functional stability of Treg cells. Specifically, IL-33-deficient Treg cells demonstrated attenuated suppressive properties in vivo and facilitated tumor regression in a suppression of tumorigenicity 2 receptor (ST2) (IL-33 receptor)-independent fashion. On activation, Il33-/- Treg cells exhibited epigenetic re-programming with increased chromatin accessibility of the Ifng locus, leading to elevated interferon (IFN)-γ production in a nuclear factor (NF)-κB-T-bet-dependent manner. IFN-γ was essential for Treg cell defective function because its ablation restored Il33-/- Treg cell-suppressive properties. Importantly, genetic ablation of Il33 potentiated the therapeutic effect of immunotherapy. Our findings reveal a new and therapeutically important intrinsic role of IL-33 in Treg cell stability in cancer.
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Interferón gamma/inmunología , Interleucina-33/inmunología , Melanoma Experimental/inmunología , Linfocitos T Reguladores/inmunología , Escape del Tumor/inmunología , Animales , Línea Celular Tumoral , Interferón gamma/genética , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismoRESUMEN
CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4+ T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis.
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Moléculas de Adhesión Celular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Homeostasis , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunomodulación , Animales , Moléculas de Adhesión Celular/genética , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Proteínas de la Matriz Extracelular/genética , Expresión Génica , Técnicas de Inactivación de Genes , Homeostasis/inmunología , Humanos , Inmunosenescencia , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Vía de Señalización WntRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
What defines regulatory T (Treg) cells in healthy human tissues? In this issue of Immunity, Delacher et al. describe a human follicular helper T cell-like tissue-repair Treg cell signature governed by BATF based on chromatin accessibility data and link this on a transcriptome and protein level to important functional features like CCR8 expression.
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Cromatina , Linfocitos T Reguladores , Humanos , TranscriptomaRESUMEN
Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.
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Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adolescente , Adulto , Anciano , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Citometría de Flujo , Células HEK293 , VIH/fisiología , Infecciones por VIH/genética , Infecciones por VIH/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Immunoblotting , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores del Factor de Necrosis Tumoral/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Transcriptoma/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Adulto JovenRESUMEN
Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.
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Dinoprostona/análogos & derivados , Dinoprostona/metabolismo , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Grasa Intraabdominal/inmunología , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunología , Células 3T3 , Animales , Línea Celular , Diabetes Mellitus Tipo 2/metabolismo , Células HEK293 , Homeostasis/inmunología , Humanos , Hidroxiprostaglandina Deshidrogenasas/genética , Resistencia a la Insulina/genética , Grasa Intraabdominal/citología , Células Jurkat , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Noqueados , Factor de Transcripción STAT5/metabolismoRESUMEN
Microglia, the major population of brain-resident macrophages, are now recognized as a heterogeneous population comprising several cell subtypes with different (so far mostly supposed) functions in health and disease. A number of studies have performed molecular characterization of these different microglial activation states over the last years making use of "omics" technologies, that is transcriptomics, proteomics and, less frequently, epigenomics profiling. These approaches offer the possibility to identify disease mechanisms, discover novel diagnostic biomarkers, and develop new therapeutic strategies. Here, we focus on epigenetic profiling as a means to understand microglial immune responses beyond what other omics methods can offer, that is, revealing past and present molecular responses, gene regulatory networks and potential future response trajectories, and defining cell subtype-specific disease relevance through mapping non-coding genetic variants. We review the current knowledge in the field regarding epigenetic regulation of microglial identity and function, provide an exemplary analysis that demonstrates the advantages of performing joint transcriptomic and epigenomic profiling of single microglial cells and discuss how comprehensive epigenetic analyses may enhance our understanding of microglial pathophysiology.
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Epigénesis Genética , Microglía , Microglía/inmunología , Microglía/metabolismo , Humanos , Animales , Epigenómica/métodos , Transcriptoma , Inmunidad/genética , Redes Reguladoras de Genes , Perfilación de la Expresión Génica , Encéfalo/inmunología , Encéfalo/metabolismoRESUMEN
High-density lipoprotein (HDL) mediates reverse cholesterol transport and is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional regulator ATF3, as an HDL-inducible target gene in macrophages that downregulates the expression of Toll-like receptor (TLR)-induced proinflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of new HDL-based therapies.
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Factor de Transcripción Activador 3/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Aterosclerosis/terapia , Colesterol/metabolismo , Inflamación/terapia , Lipoproteínas HDL/uso terapéutico , Macrófagos/efectos de los fármacos , Factor de Transcripción Activador 3/genética , Animales , Antiinflamatorios no Esteroideos/farmacología , Células Cultivadas , Inmunoprecipitación de Cromatina , Citocinas/metabolismo , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lipoproteínas HDL/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Biología de Sistemas , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunologíaRESUMEN
Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies.
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Células Dendríticas/inmunología , Interleucina-4/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Co-Represor 2 de Receptor Nuclear/inmunología , Transducción de Señal/inmunología , Diferenciación Celular , Linaje de la Célula , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Inmunofenotipificación , Interleucina-4/genética , Interleucina-4/farmacología , Activación de Macrófagos , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Monocitos/citología , Monocitos/efectos de los fármacos , Co-Represor 2 de Receptor Nuclear/genética , Cultivo Primario de Células , Factores de Tiempo , Transcripción GenéticaRESUMEN
Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune-cell checkpoint receptor/ligand pair PD-1/PD-L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD-L1 and PD-1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD-L1 from astrocytes, which may mediate ectodomain signaling to PD-1-expressing microglia. Deletion of microglial PD-1 evoked an inflammatory response and compromised amyloid-ß peptide (Aß) uptake. APP/PS1 mice deficient for PD-1 exhibited increased deposition of Aß, reduced microglial Aß uptake, and decreased expression of the Aß receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD-1/PD-L1 axis contributes to Aß plaque deposition during chronic neuroinflammation in AD.
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Enfermedad de Alzheimer/inmunología , Precursor de Proteína beta-Amiloide/genética , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Regulación hacia Arriba , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/toxicidad , Animales , Astrocitos/metabolismo , Antígenos CD36/metabolismo , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Células HEK293 , Células HeLa , Humanos , Masculino , Ratones , Ratones Transgénicos , Microglía/metabolismo , Persona de Mediana EdadRESUMEN
Lineage commitment during myelopoiesis has been linked to late-stage progenitors with multi-lineage potential. In a recent issue of Cell, Paul et al. (2015) now suggest a much earlier commitment toward distinct lineages even prior to the common myeloid progenitor state.