RESUMEN
Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aß plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aß plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3ß-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aß involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.
Asunto(s)
Enfermedad de Alzheimer , Microglía , Animales , Ratones , Humanos , Microglía/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/patología , Placa Amiloide/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Quinasa Syk/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismoRESUMEN
Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
Asunto(s)
Neoplasias de la Mama , Macrófagos , Mama/inmunología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/inmunología , Linfocitos T CD8-positivos , Femenino , Receptor 2 de Folato , Humanos , Linfocitos Infiltrantes de Tumor , PronósticoRESUMEN
Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2-/- mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.
Asunto(s)
Inmunoterapia , Glicoproteínas de Membrana/metabolismo , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Receptor 1 de Quimiocinas CX3C/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/metabolismo , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Metilcolantreno/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/inducido químicamente , Neoplasias/patología , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Microambiente TumoralRESUMEN
Cell function and activity are regulated through integration of signaling, epigenetic, transcriptional, and metabolic pathways. Here, we introduce INs-seq, an integrated technology for massively parallel recording of single-cell RNA sequencing (scRNA-seq) and intracellular protein activity. We demonstrate the broad utility of INs-seq for discovering new immune subsets by profiling different intracellular signatures of immune signaling, transcription factor combinations, and metabolic activity. Comprehensive mapping of Arginase 1-expressing cells within tumor models, a metabolic immune signature of suppressive activity, discovers novel Arg1+ Trem2+ regulatory myeloid (Mreg) cells and identifies markers, metabolic activity, and pathways associated with these cells. Genetic ablation of Trem2 in mice inhibits accumulation of intra-tumoral Mreg cells, leading to a marked decrease in dysfunctional CD8+ T cells and reduced tumor growth. This study establishes INs-seq as a broadly applicable technology for elucidating integrated transcriptional and intra-cellular maps and identifies the molecular signature of myeloid suppressive cells in tumors.
Asunto(s)
Glicoproteínas de Membrana/metabolismo , Neoplasias/patología , ARN Citoplasmático Pequeño/química , Receptores Inmunológicos/metabolismo , Animales , Arginasa/genética , Arginasa/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/metabolismo , ARN Citoplasmático Pequeño/metabolismo , Receptores Inmunológicos/genética , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Factores de Transcripción/metabolismo , Microambiente Tumoral , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
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.
Asunto(s)
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
Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.
Asunto(s)
Enfermedad de Alzheimer , Microglía , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Metabolismo Energético , Microglía/metabolismo , Neuronas/metabolismo , Animales , RatonesRESUMEN
Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1ß in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Hipernutrición , Humanos , Enfermedad del Hígado Graso no Alcohólico/patología , Hipernutrición/patología , Hígado/patología , Inflamación/patología , Obesidad/patología , Glicoproteínas de Membrana , Receptores InmunológicosRESUMEN
Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density of the complexes was associated with lower deposition of C3 but higher amounts of synaptic proteins. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapses and accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, which we identified to be responsible for TREM2 binding to C1q, rescued synaptic impairments in AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restricting complement-mediated synaptic elimination during neurodegeneration, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis.
Asunto(s)
Enfermedad de Alzheimer , Complemento C1q , Ratones , Animales , Humanos , Complemento C1q/genética , Complemento C1q/metabolismo , Encéfalo/metabolismo , Sinapsis/metabolismo , Activación de Complemento , Microglía/metabolismo , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismoRESUMEN
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-ß pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.
Asunto(s)
Enfermedad de Alzheimer/patología , Metabolismo Energético , Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Autofagia , Creatinina/análogos & derivados , Creatinina/metabolismo , Modelos Animales de Enfermedad , Humanos , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Microglía/patología , Neuritas/metabolismo , Placa Amiloide/metabolismo , Receptores Inmunológicos/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Mononuclear phagocytes (MNPs) encompass dendritic cells, monocytes, and macrophages (MoMac), which exhibit antimicrobial, homeostatic, and immunoregulatory functions. We integrated 178,651 MNPs from 13 tissues across 41 datasets to generate a MNP single-cell RNA compendium (MNP-VERSE), a publicly available tool to map MNPs and define conserved gene signatures of MNP populations. Next, we generated a MoMac-focused compendium that revealed an array of specialized cell subsets widely distributed across multiple tissues. Specific pathological forms were expanded in cancer and inflammation. All neoplastic tissues contained conserved tumor-associated macrophage populations. In particular, we focused on IL4I1+CD274(PD-L1)+IDO1+ macrophages, which accumulated in the tumor periphery in a T cell-dependent manner via interferon-γ (IFN-γ) and CD40/CD40L-induced maturation from IFN-primed monocytes. IL4I1_Macs exhibited immunosuppressive characteristics through tryptophan degradation and promoted the entry of regulatory T cell into tumors. This integrated analysis provides a robust online-available platform for uniform annotation and dissection of specific macrophage functions in healthy and pathological states.
Asunto(s)
Células Dendríticas/inmunología , Expresión Génica/inmunología , Monocitos/inmunología , Transcriptoma/genética , Macrófagos Asociados a Tumores/inmunología , Artritis Reumatoide/inmunología , COVID-19/inmunología , Expresión Génica/genética , Perfilación de la Expresión Génica , Humanos , Interferón gamma/inmunología , L-Aminoácido Oxidasa/metabolismo , Cirrosis Hepática/inmunología , Macrófagos/inmunología , Neoplasias/inmunología , ARN Citoplasmático Pequeño/genética , Análisis de la Célula Individual , Linfocitos T Reguladores/inmunología , Transcriptoma/inmunologíaRESUMEN
Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.
Asunto(s)
Microambiente Celular/genética , Reprogramación Celular/genética , Epigénesis Genética , Regulación de la Expresión Génica , Células Mieloides/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Biomarcadores , Secuenciación de Inmunoprecipitación de Cromatina , Dieta , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Ontología de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Macrófagos del Hígado/inmunología , Macrófagos del Hígado/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/patología , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Unión Proteica , Transducción de Señal , Análisis de la Célula IndividualRESUMEN
The development and functional potential of metazoan cells is dependent on combinatorial roles of transcriptional enhancers and promoters. Macrophages provide exceptionally powerful model systems for investigation of mechanisms underlying the activation of cell-specific enhancers that drive transitions in cell fate and cell state. Here, we review recent advances that have expanded appreciation of the diversity of macrophage phenotypes in health and disease, emphasizing studies of liver, adipose tissue, and brain macrophages as paradigms for other tissue macrophages and cell types. Studies of normal tissue-resident macrophages and macrophages associated with cirrhosis, obese adipose tissue, and neurodegenerative disease illustrate the major roles of tissue environment in remodeling enhancer landscapes to specify the development and functions of distinct macrophage phenotypes. We discuss the utility of quantitative analysis of environment-dependent changes in enhancer activity states as an approach to discovery of regulatory transcription factors and upstream signaling pathways.
Asunto(s)
Elementos de Facilitación Genéticos , Macrófagos/metabolismo , Microglía/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Activación Transcripcional , Animales , Linaje de la Célula , Microambiente Celular , Humanos , Macrófagos/patología , Microglía/patología , Fenotipo , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-ß, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.
Asunto(s)
Enfermedades Neurodegenerativas/inmunología , Transducción de Señal/inmunología , Envejecimiento/inmunología , Animales , Activación de Complemento , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Gliosis/inmunología , Gliosis/patología , Humanos , Inmunidad Innata , Inflamación/inmunología , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Microglía/inmunología , Modelos Inmunológicos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/terapia , Agregación Patológica de Proteínas/inmunología , Receptores Inmunológicos/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
Advances in human genetics have implicated a growing number of genes in neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease in particular, genome-wide association studies and gene expression studies have emphasized the pathogenic contributions from microglial cells and motivated studies of microglial function/dysfunction. Here, we summarize recent genetic evidence for microglial involvement in neurodegenerative disease with a focus on Alzheimer disease, for which the evidence is most compelling. To provide context for these genetic discoveries, we discuss how microglia influence brain development and homeostasis, how microglial characteristics change in disease, and which microglial activities likely influence the course of neurodegeneration. In all, we aim to synthesize varied aspects of microglial biology and highlight microglia as possible targets for therapeutic interventions in neurodegenerative disease.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Microglía/patología , Microglía/fisiología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/fisiopatología , Envejecimiento/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Animales , Encéfalo/fisiología , Sistema Nervioso Central/metabolismo , Vía Clásica del Complemento/fisiología , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Homeostasis , Humanos , Macrófagos/fisiología , Placa Amiloide/fisiopatología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2-/- mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases.
Asunto(s)
Encéfalo/inmunología , Glicoproteínas de Membrana/inmunología , Microglía/inmunología , Neuronas/inmunología , Receptores Inmunológicos/inmunología , Sinapsis/inmunología , Animales , Trastorno Autístico/genética , Trastorno Autístico/inmunología , Trastorno Autístico/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Células Cultivadas , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/citología , Microglía/metabolismo , Neuronas/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica/genética , Transmisión Sináptica/inmunologíaRESUMEN
Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.
Asunto(s)
Comunicación Celular/genética , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Análisis de Secuencia de ARN , Animales , Reprogramación Celular/genética , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Humanos , Ligandos , Hígado/patología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal/genética , Análisis de la Célula IndividualRESUMEN
TREM2 is a myeloid cell receptor that has been extensively described in the context of neuroinflammation and neurodegenerative diseases. Recently, TREM2 emerged as a crucial regulator of macrophage function in tumors. TREM2-deficiency or blockade provide protection and promote the response to anti-PD1 in different murine models. In human tumors, TREM2-expressing macrophages are present in numerous cohorts and tumor types and are generally associated with immunosuppression and poor prognosis. Here, we provide an overview of the impact of TREM2 in tumors considering current literature, with a focus on both murine models and human cancer.
Asunto(s)
Enfermedades Neurodegenerativas , Microambiente Tumoral , Humanos , Ratones , Animales , Macrófagos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Células Mieloides , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/genéticaRESUMEN
While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.
Asunto(s)
Macrófagos del Hígado , Cirrosis Hepática , Macrófagos , Glicoproteínas de Membrana , Receptores Inmunológicos , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Animales , Ratones , Macrófagos/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Masculino , Lípidos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/genética , Ratones NoqueadosRESUMEN
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic ß-amyloid (Aß)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
Asunto(s)
Apolipoproteínas E/metabolismo , Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Receptores Inmunológicos/metabolismo , Transducción de Señal , Transcriptoma , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Apoptosis/genética , Apoptosis/inmunología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Análisis por Conglomerados , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Marcación de Gen , Humanos , Tolerancia Inmunológica , Ratones , Ratones Noqueados , Ratones Transgénicos , Microglía/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Enfermedades Neurodegenerativas/inmunología , Neuronas/metabolismo , Fagocitosis/genética , Fagocitosis/inmunología , Fenotipo , Placa Amiloide/metabolismo , Placa Amiloide/patología , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
ITM2B/BRI2 mutations cause Alzheimer's Disease (AD)-related dementias. We observe heightened ITM2B/BRI2 expression in microglia, a pivotal cell type in AD due to risk-increasing variants in the microglial gene TREM2. Single-cell RNA-sequencing demonstrates a Trem2/Bri2-dependent microglia cluster, underscoring their functional interaction. α-secretase cleaves TREM2 into TREM2-CTF and sTREM2. As BRI2 hinders α-secretase cleavage of the AD-related Aß-Precursor-Protein, we probed whether BRI2 influences TREM2 processing. Our findings indicate a BRI2-TREM2 interaction that inhibits TREM2 processing in heterologous cells. Recombinant BRI2 and TREM2 proteins demonstrate a direct, cell-free BRI2-TREM2 ectodomain interaction. Constitutive and microglial-specific Itm2b-Knock-out mice, and Itm2b-Knock-out primary microglia provide evidence that Bri2 reduces Trem2 processing, boosts Trem2 mRNA expression, and influences Trem2 protein levels through α-secretase-independent pathways, revealing a multifaceted BRI2-TREM2 functional interaction. Moreover, a mutant Itm2b dementia mouse model exhibits elevated Trem2-CTF and sTrem2, mirroring sTREM2 increases in AD patients. Lastly, Bri2 deletion reduces phagocytosis similarly to a pathogenic TREM2 variant that enhances processing. Given BRI2's role in regulating Aß-Precursor-Protein and TREM2 functions, it holds promise as a therapeutic target for AD and related dementias.