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1.
Cell ; 186(17): 3706-3725.e29, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37562402

RESUMO

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.


Assuntos
Medula Óssea , Doenças do Sistema Nervoso , Crânio , Animais , Humanos , Camundongos , Medula Óssea/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/metabolismo , Crânio/citologia , Crânio/diagnóstico por imagem
2.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34037669

RESUMO

Neuroinflammation is an emerging focus of translational stroke research. Preclinical studies have demonstrated a critical role for brain-invading lymphocytes in post-stroke pathophysiology. Reducing cerebral lymphocyte invasion by anti-CD49d antibodies consistently improves outcome in the acute phase after experimental stroke models. However, clinical trials testing this approach failed to show efficacy in stroke patients for the chronic outcome 3 mo after stroke. Here, we identify a potential mechanistic reason for this phenomenon by detecting chronic T cell accumulation-evading the systemic therapy-in the post-ischemic brain. We observed a persistent accumulation of T cells in mice and human autopsy samples for more than 1 mo after stroke. Cerebral T cell accumulation in the post-ischemic brain was driven by increased local T cell proliferation rather than by T cell invasion. This observation urges re-evaluation of current immunotherapeutic approaches, which target circulating lymphocytes for promoting recovery after stroke.


Assuntos
Encéfalo/imunologia , Encéfalo/patologia , Imunoterapia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Linfócitos T/imunologia , Animais , Autopsia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Proliferação de Células , Feminino , Humanos , Integrina alfa4/imunologia , Contagem de Linfócitos , Masculino , Camundongos Endogâmicos C57BL , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/fisiopatologia
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