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1.
Cell ; 186(20): 4386-4403.e29, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37774678

RESUMO

Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects and diverse Alzheimer's disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.


Assuntos
Doença de Alzheimer , Microglia , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Regulação da Expressão Gênica , Inflamação/patologia , Microglia/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Epigenoma
2.
Proc Natl Acad Sci U S A ; 117(5): 2570-2578, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31964813

RESUMO

The thymus generates cells of the T cell lineage that seed the lymphatic and blood systems. Transcription factor regulatory networks control the lineage programming and maturation of thymic precursor cells. Whether extrathymic antigenic events, such as the microbial colonization of the mucosal tract also shape the thymic T cell repertoire is unclear. We show here that intestinal microbes influence the thymic homeostasis of PLZF-expressing cells in early life. Impaired thymic development of PLZF+ innate lymphocytes in germ-free (GF) neonatal mice is restored by colonization with a human commensal, Bacteroides fragilis, but not with a polysaccharide A (PSA) deficient isogenic strain. Plasmacytoid dendritic cells influenced by microbes migrate from the colon to the thymus in early life to regulate PLZF+ cell homeostasis. Importantly, perturbations in thymic PLZF+ cells brought about by alterations in early gut microbiota persist into adulthood and are associated with increased susceptibility to experimental colitis. Our studies identify a pathway of communication between intestinal microbes and thymic lymphocytes in the neonatal period that can modulate host susceptibility to immune-mediated diseases later in life.


Assuntos
Microbioma Gastrointestinal , Linfócitos/imunologia , Timo/crescimento & desenvolvimento , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bacteroides fragilis/fisiologia , Diferenciação Celular , Colite/genética , Colite/imunologia , Colite/microbiologia , Colo/microbiologia , Humanos , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Timo/citologia , Timo/imunologia
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