RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT

• 成果类型: Article
• 署名作者: Cao, Ze; Min, Xia; Xie, Xingxing; Huang, Maoqing; Liu, Yingying; Sun, Weimin; Xu, Guifang; He, Miao; He, Kaiwen; Li, Ying; Yuan, Junying
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Fudan University; Fudan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10727
• DOI: 10.1073/pnas.2320383121
• 发表日期: 2024-02-06
• 关键词: rett-syndrome microglia; mouse model; mitochondrial dysfunction; binding-protein; system x(c)(-); necroptosis; kinase; mecp2; brain; localization

摘要

Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor- Interacting Serine/Threonine- Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2- deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2- deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2- deficient microglia release high levels of glutamate to impair glutamate- mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2- deficient microglia may be involved both in the onset and progression of RTT.