ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Cellular and Molecular Mechanisms of Brain-aging
This article is part of the Research TopicMitochondrial Dysfunction in Cellular and Molecular Mechanisms of Brain AgingView all 3 articles
Single-cell analysis of microglial activation after traumatic brain injury reveals immune signaling pathways linked to mitochondrial dysfunction and brain aging
Provisionally accepted
- 1The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- 2Shenzhen Children's Hospital, Shenzhen, China
- 3The First Affiliated Hospital of Soochow University, Suzhou, China
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Objective: Microglia are the primary immune cells in the central nervous system (CNS), yet their temporal and spatial responses to traumatic brain injury (TBI) at the single-cell level remain poorly defined. This study aimed to map dynamic microglial responses to TBI using single-cell transcriptomics and validate key signaling pathways in-vitro. Methods: A single-cell transcriptomic atlas was reconstructed from publicly available datasets comprising cortical, hippocampal, and blood samples from 35 mice (11 blood, 12 cortex, 12 hippocampus) subjected to TBI or sham treatment at 24 hours and 7 days. Comparative analyses were conducted to investigate myeloid cell heterogeneity, including monocytes, macrophages, and microglia, with a focus on activated microglia. Key findings were further validated using quantitative PCR (qPCR) in an in-vitro TBI-mimicking model, employing lipopolysaccharide (LPS) stimulated microglial cell lines to assess gene expression changes. Results: TBI induced rapid immune remodeling, including increased activated microglia in the cortex enriched in leukocyte differentiation pathways, and elevated macrophage populations in cortex and hippocampus enriched in chemotaxis functions at 24 hours. Ligand–receptor analysis revealed three majors signaling axes Ccl2/Ccl7/Ccr2, Tnf/Tnfrsf1b, and Grn/Flna implicated in monocyte recruitment, M1 polarization, and macrophage differentiation. qPCR validation confirmed significant upregulation of Ccl2, Tnf, and Grn in LPS-stimulated microglia, consistent with single-cell findings Conclusion: This work provides the first integrative single-cell transcriptomic map of microglial–myeloid interactions after TBI across multiple tissues and time points, linking microglial signaling to mitochondrial dysfunction and neuroinflammation. These insights lay the foundation for therapeutic strategies targeting myeloid-driven immune regulation in TBI.
Keywords: microglia activation, Myeloid Response, Neuroinflammation, Single-cell transcriptomics, Traumatic Brain Injury
Received: 01 Jul 2025; Accepted: 11 Dec 2025.
Copyright: © 2025 Sun, Wu, Wu, Liu, Gu, Wang, Yang and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Feng Xu
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