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1.
Immunity ; 57(7): 1696-1709.e10, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38878770

RESUMO

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.


Assuntos
Encéfalo , Interferon-alfa , Microvasos , Malformações do Sistema Nervoso , Receptor de Interferon alfa e beta , Animais , Humanos , Camundongos , Interferon-alfa/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Receptor de Interferon alfa e beta/metabolismo , Receptor de Interferon alfa e beta/genética , Microvasos/patologia , Malformações do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Células Endoteliais/metabolismo , Camundongos Knockout , Masculino , Feminino , Transdução de Sinais , Camundongos Endogâmicos C57BL , Astrócitos/metabolismo , Modelos Animais de Doenças
2.
Neuropathol Appl Neurobiol ; 50(4): e13003, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39075830

RESUMO

Previous reports have shown that IL-6 and IFN-⍺ induce distinct transcriptomic and morphological changes in microglia. Here, we demonstrate that IL-6 increases tissue surveillance, migration and phagocytosis in primary murine microglia, whereas IFN-⍺ inhibits these functions. Our results provide a crucial link between transcriptome and function. It holds the potential to serve as the foundation for future studies aimed at identifying therapeutic targets for cytokine-mediated neuroinflammatory diseases.


Assuntos
Interferon-alfa , Interleucina-6 , Microglia , Animais , Camundongos , Movimento Celular/efeitos dos fármacos , Interferon-alfa/metabolismo , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/efeitos dos fármacos , Fagocitose/fisiologia , Fagocitose/efeitos dos fármacos
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