Aging-dependent microglial heterogeneity worsens outcomes in models of traumatic brain injury
Zhichao Lu, Yi Shuai, Chenxing Wang, Zongheng Liu, Ziheng Wang, Qianqian Liu, Rui Jiang, Jue Zhu, Yongqi Zhu, Weiquan Liao, Xingjia Zhu, Jingwei Zhao, Kaibin Shi, Wei Shi, Peipei Gong
Zhichao Lu, Yi Shuai, Chenxing Wang, Zongheng Liu, Ziheng Wang, Qianqian Liu, Rui Jiang, Jue Zhu, Yongqi Zhu, Weiquan Liao, Xingjia Zhu, Jingwei Zhao, Kaibin Shi, Wei Shi, Peipei Gong
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Research Article Immunology Inflammation Neuroscience

Aging-dependent microglial heterogeneity worsens outcomes in models of traumatic brain injury

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.

Authors

Zhichao Lu, Yi Shuai, Chenxing Wang, Zongheng Liu, Ziheng Wang, Qianqian Liu, Rui Jiang, Jue Zhu, Yongqi Zhu, Weiquan Liao, Xingjia Zhu, Jingwei Zhao, Kaibin Shi, Wei Shi, Peipei Gong

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