Aging-dependent microglial heterogeneity worsens outcomes in models of traumatic brain injury
Zhichao Lu1,2, Yi Shuai3, Chenxing Wang1,2
1Department of Neurosurgery, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
Abstract:
Traumatic brain injury (TBI) disproportionately affects the elderly, yet the underlying mechanisms remain unclear. Here, we demonstrate that aged TBI brains predominantly harbor proinflammatory NLRP3+ microglia, in stark contrast to the neuroprotective Lysozyme+ microglia prevalent in young TBI brains. This age-dependent microglial dichotomy correlates with elevated mortality and impaired recovery in aged TBI mice. By leveraging an integrative multiomics approach combined with metabolomics and epigenome analysis, we identified a previously unrecognized link between enhanced glycolysis and the proinflammatory chromatin landscape in NLRP3+ microglia. Further investigation identified ELF1 as a key transcription factor driving NLRP3+ microglia formation. Importantly, ablation of ELF1 reversed age-associated microglial dysfunction and improved TBI outcomes. Finally, we report that Imeglimin, a clinically approved antihyperglycemic agent capable of crossing the blood-brain barrier, inhibits ELF1 and reverses microglial phenotype, reducing acute mortality rate and leading to improved functional recovery of aged mice with TBI. Our work elucidates the mechanistic basis of age-dependent TBI outcomes, reveals the crosstalk between metabolic rewiring and epigenetic regulation in microglial aging, and identifies ELF1 as a promising therapeutic target for improving TBI outcomes.
Insights
Aged traumatic brain injury (TBI) brains show harmful NLRP3+ microglia, unlike young brains. Targeting ELF1 with Imeglimin improves recovery in elderly TBI mice.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Traumatic brain injury (TBI) disproportionately impacts the elderly, with unclear underlying mechanisms.
- Aged TBI brains exhibit pro-inflammatory NLRP3+ microglia, contrasting with neuroprotective Lysozyme+ microglia in young TBI brains.
- This microglial difference in aging correlates with increased mortality and worsened recovery in aged TBI models.
Purpose of the Study:
- To elucidate the mechanisms behind age-dependent TBI outcomes.
- To investigate the link between metabolic changes, epigenetic regulation, and microglial aging in TBI.
- To identify therapeutic targets for improving TBI outcomes in the elderly.
Main Methods:
- Integrative multi-omics, metabolomics, and epigenome analysis in aged and young TBI mouse models.
- Identification and functional assessment of key transcription factors involved in microglial polarization.
- Pharmacological intervention using Imeglimin, a blood-brain barrier-penetrant antihyperglycemic agent.
Main Results:
- Aged TBI brains show a shift towards pro-inflammatory NLRP3+ microglia, driven by enhanced glycolysis and a pro-inflammatory chromatin landscape.
- ELF1 identified as a crucial transcription factor for NLRP3+ microglia formation.
- Ablation of ELF1 reversed age-associated microglial dysfunction and improved TBI outcomes.
- Imeglimin treatment inhibited ELF1, reversed microglial phenotype, reduced mortality, and enhanced functional recovery in aged TBI mice.
Conclusions:
- Age-dependent microglial polarization significantly impacts TBI outcomes.
- Metabolic rewiring and epigenetic regulation are key in microglial aging and TBI response.
- ELF1 is a critical mediator of age-related microglial dysfunction in TBI.
- Imeglimin shows therapeutic potential for mitigating TBI effects in the elderly by targeting ELF1-mediated pathways.
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