Tripathi Ajai, Rai Nagendra Kumar, Perles Aaron, Courtney Haley, Jones Claire, Sapra Adya, Plemel Jason, Dutta Ranjan
Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA.
Neuroscience and Mental Health Institute, Department of Medicine, Division of Neurology, Department of Medical Microbiology and Immunology, University of Alberta, Canada.
Neurobiol Dis. 2025 May;208:106879. doi: 10.1016/j.nbd.2025.106879. Epub 2025 Mar 20.
Microglia are essential regulators of central nervous system (CNS) homeostasis, playing key roles in demyelination and remyelination. Dysregulated microglial activity contributes to pathological inflammation and impaired repair processes in demyelinating diseases. Here, we investigate the role of Dicer1, a critical enzyme in microRNA biogenesis, in affecting microglial function, demyelination, and remyelination. Loss of Dicer1 in microglia resulted in amplified inflammatory responses, defective myelin debris clearance, and disruption of metabolic homeostasis, leading to exacerbated demyelination and delayed remyelination. Transcriptomic analysis revealed significant upregulation of inflammatory pathways, including interferon signaling and JAK/STAT activation, alongside a loss of homeostatic microglial gene expression. Protein-level validation confirmed sustained secretion of pro-inflammatory cytokines such as IFN-γ, IL-16, and CXCL12, creating a chronic inflammatory environment that impaired remyelination. Furthermore, Dicer1-deficient microglia failed to support oligodendrocyte progenitor cells (OPCs) differentiation/maturation, with increased apoptosis of mature oligodendrocytes (OLs), contributing to remyelination failure. These findings identify Dicer1 as a critical regulator of microglial homeostasis and inflammation resolution, highlighting its potential as a therapeutic target to mitigate inflammation and promote repair in demyelinating diseases.
小胶质细胞是中枢神经系统（CNS）稳态的重要调节因子，在脱髓鞘和髓鞘再生中发挥关键作用。小胶质细胞活性失调会导致病理性炎症，并损害脱髓鞘疾病中的修复过程。在此，我们研究了Dicer1（一种微小RNA生物发生中的关键酶）在影响小胶质细胞功能、脱髓鞘和髓鞘再生方面的作用。小胶质细胞中Dicer1的缺失导致炎症反应放大、髓鞘碎片清除缺陷以及代谢稳态破坏，进而导致脱髓鞘加剧和髓鞘再生延迟。转录组分析显示炎症通路显著上调，包括干扰素信号传导和JAK/STAT激活，同时稳态小胶质细胞基因表达丧失。蛋白质水平验证证实促炎细胞因子如IFN-γ、IL-16和CXCL12持续分泌，形成了损害髓鞘再生的慢性炎症环境。此外，Dicer1缺陷的小胶质细胞无法支持少突胶质前体细胞（OPCs）的分化/成熟，成熟少突胶质细胞（OLs）的凋亡增加，导致髓鞘再生失败。这些发现确定Dicer1是小胶质细胞稳态和炎症消退的关键调节因子，突出了其作为减轻脱髓鞘疾病炎症和促进修复的治疗靶点的潜力。
