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J Exp Med ; 218(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33045062

RESUMO

The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia's phagocytic activity under demyelinating conditions.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/metabolismo , Microglia/metabolismo , Fagocitose , Estabilidade de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Antígenos CD36/genética , Antígenos CD36/metabolismo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/genética , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Humanos , Camundongos , Camundongos Transgênicos , Microglia/patologia , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fagossomos/genética , Fagossomos/metabolismo , Fagossomos/patologia , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética
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