Dicer deficiency affects microglial function during demyelination and impairs remyelination
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 Di...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000956 |
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| author | Ajai Tripathi Nagendra Kumar Rai Aaron Perles Haley Courtney Claire Jones Adya Sapra Jason Plemel Ranjan Dutta |
| author_facet | Ajai Tripathi Nagendra Kumar Rai Aaron Perles Haley Courtney Claire Jones Adya Sapra Jason Plemel Ranjan Dutta |
| author_sort | Ajai Tripathi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e20ae64bce0b43b2ae85a260f15d5d0f |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-e20ae64bce0b43b2ae85a260f15d5d0f2025-08-20T02:16:27ZengElsevierNeurobiology of Disease1095-953X2025-05-0120810687910.1016/j.nbd.2025.106879Dicer deficiency affects microglial function during demyelination and impairs remyelinationAjai Tripathi0Nagendra Kumar Rai1Aaron Perles2Haley Courtney3Claire Jones4Adya Sapra5Jason Plemel6Ranjan Dutta7Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USADepartment of Neurosciences, Cleveland Clinic, Cleveland, OH, USADepartment of Neurosciences, Cleveland Clinic, Cleveland, OH, USADepartment of Neurosciences, Cleveland Clinic, Cleveland, OH, USADepartment of Neurosciences, Cleveland Clinic, Cleveland, OH, USADepartment of Neurosciences, Cleveland Clinic, Cleveland, OH, USANeuroscience and Mental Health Institute, Department of Medicine, Division of Neurology, Department of Medical Microbiology and Immunology, University of Alberta, CanadaDepartment of Neurosciences, Cleveland Clinic, Cleveland, OH, USA; Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA; Corresponding author at: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/ NC30, Cleveland, OH 44195, USA.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.http://www.sciencedirect.com/science/article/pii/S0969996125000956MicrogliaDicer1microRNACytokinesInflammationDemyelination |
| spellingShingle | Ajai Tripathi Nagendra Kumar Rai Aaron Perles Haley Courtney Claire Jones Adya Sapra Jason Plemel Ranjan Dutta Dicer deficiency affects microglial function during demyelination and impairs remyelination Neurobiology of Disease Microglia Dicer1 microRNA Cytokines Inflammation Demyelination |
| title | Dicer deficiency affects microglial function during demyelination and impairs remyelination |
| title_full | Dicer deficiency affects microglial function during demyelination and impairs remyelination |
| title_fullStr | Dicer deficiency affects microglial function during demyelination and impairs remyelination |
| title_full_unstemmed | Dicer deficiency affects microglial function during demyelination and impairs remyelination |
| title_short | Dicer deficiency affects microglial function during demyelination and impairs remyelination |
| title_sort | dicer deficiency affects microglial function during demyelination and impairs remyelination |
| topic | Microglia Dicer1 microRNA Cytokines Inflammation Demyelination |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000956 |
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