RESUMO
Trained immunity is a form of innate immune memory with distinct features from classical adaptive immune memory. In the current issues of Cell and Cell Host & Microbe, five studies from the International Trained Immunity Consortium shed light on mechanisms and functional consequences of this phenomenon on cellular and whole-organism levels.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Humanos , Doenças do Sistema Imunitário , Memória Imunológica , Ácido MevalônicoRESUMO
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.
Assuntos
Doença de Alzheimer/patologia , Metabolismo Energético , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Doença de Alzheimer/metabolismo , Animais , Autofagia , Creatinina/análogos & derivados , Creatinina/metabolismo , Modelos Animais de Doenças , Humanos , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Microglia/patologia , Neuritos/metabolismo , Placa Amiloide/metabolismo , Receptores Imunológicos/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
The predominant type of immune cell in the brain is the microglia, a type of tissue-resident macrophage. In a variety of neurodegenerative settings, microglia alter their transcriptional profile, morphology and function in similar ways; thus, these activated cells have been called 'degeneration- or disease-associated microglia' (DAM). These activated microglia can perform different functions and exert both positive effects and negative effects in different mouse disease models. In humans, mutations in genes expressed in microglia are linked to various neurodegenerative diseases. Here we provide an overview of the common microglial response to neurodegeneration and key contributing pathways; delineate the multifaceted functions of activated microglia spanning various diseases; and discuss insights from the study of human disease-associated genes. We argue that strong evidence from both mouse models and human genetics causally links the function of activated microglia to neurodegeneration.
Assuntos
Microglia , Doenças Neurodegenerativas , Animais , HumanosRESUMO
Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB.
Assuntos
Diferenciação Celular , Neoplasias Colorretais , Memória Imunológica , Células Matadoras Naturais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Humanos , Animais , Camundongos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Interferon gama/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Camundongos Endogâmicos NOD , FemininoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Transcriptoma/genética , Idoso , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Axônios/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Pessoa de Meia-Idade , Degeneração Neural/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Transcrição GênicaRESUMO
Microglia are a subset of tissue macrophages that constitute the major immune cell type of the central nervous system. These cells have long been known to change their morphology and functions in response to various neurological insults. Recently, a plethora of unbiased transcriptomics studies have revealed that across a broad spectrum of neurodegeneration-like disease models, microglia adopt a similar activation signature and perform similar functions. Despite these commonalities in response, the role of microglia has been described as both positive and negative in different murine disease models. In humans, genetic association studies have revealed strong connections between microglia genes and various neurodegenerative diseases, and mechanistic investigations of these mutations have added another layer of complexity. Here, we provide an overview of studies that have built a case for a common microglial response to neurodegeneration and discuss pathways that may be important to initiate and sustain this response; delineate the multifaceted functions of activated microglia spanning different diseases; and discuss insights from studying genes associated with disease in humans. We argue that strong evidence causally links activated microglia function to neurodegeneration and discuss what seems to be a conflict between mouse models and human genetics.
Assuntos
Sistema Nervoso Central/imunologia , Macrófagos/fisiologia , Microglia/fisiologia , Doenças Neurodegenerativas/imunologia , Animais , Modelos Animais de Doenças , Estudos de Associação Genética , Humanos , Camundongos , Mutação/genética , Doenças Neurodegenerativas/genética , Transdução de Sinais , TranscriptomaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-ß plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-ß-induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-ß accumulation and R47H impairs this interaction.
Assuntos
Glicoproteínas de Membrana/genética , Microglia/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores Imunológicos/genética , Proteína ADAM17/metabolismo , Animais , Encéfalo/patologia , Contagem de Células , Gliose/genética , Gliose/patologia , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos Transgênicos , Células Mieloides/metabolismo , Células Mieloides/patologia , Neurônios/metabolismo , Receptores Imunológicos/metabolismo , SolubilidadeRESUMO
One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-ß (Aß) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aß in the brain. In addition to influencing Aß metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1ΔE9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aß morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.