OSCR

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

Overview

Authors: Zhichao Lu1,2, Yi Shuai3, Chenxing Wang1,2, Zongheng Liu4, Ziheng Wang5,6, Qianqian Liu1,2, Rui Jiang1,2, Jue Zhu1,2, Yongqi Zhu1,2, Weiquan Liao1,2, Xingjia Zhu1,2, Jingwei Zhao7, Kaibin Shi8,9, Wei Shi1,2, Peipei Gong1,2
ORCID iDs: Ziheng Wang, Jingwei Zhao
  1. Department of Neurosurgery, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
  2. Neuro-Microscopy and Minimally Invasive Translational Medicine Innovation Center, Affiliated Hospital of Nantong University, Nantong, China
  3. Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China
  4. Department of Neurosurgery, Zhejiang Provincial Hospital of Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
  5. MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau Special Administrative Region, China
  6. School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
  7. Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
  8. Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
  9. Chinese Institute for Immunology, Chinese Institutes for Medical Research, Beijing, China
Institutions: Nantong University (China); Affiliated Hospital of Nantong University (China); Chinese University of Hong Kong (Hong Kong SAR China); Zhejiang Chinese Medical University (China); University of Macau (Macao SAR China); Monash University (Australia); Shanghai Jiao Tong University (China); XinHua Hospital (China); Capital Medical University (China); Beijing Tian Tan Hospital (China)
Journal: The Journal of clinical investigation, volume 136, issue 12, article e196112
Dates: received 28 May 2025; accepted 19 March 2026; published online 2 April 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1172/jci196112 · PMID 41926211 · PMCID PMC13262727 · OpenAlex W7148533955
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), mouse (organism), traumatic brain injury (population)
Methods: Statistics, Smoothing, state filtering, decompositions, Evoked potentials, Graphs, Machine learning
Keywords: Immunology, Inflammation, Neuroscience, Drug therapy, Innate immunity, Neurodegeneration
MeSH: Aging*, Brain Injuries, Traumatic*, Microglia*, Animals, Disease Models, Animal, DNA-Binding Proteins, Humans, Male, Mice, Mice, Knockout, Transcription Factors (* major topic)
Topic: Neuroinflammation and Neurodegeneration Mechanisms (Neurology, Neuroscience), according to OpenAlex
Funding: National Natural Science Foundation of China (82301561, 82322023, 82371398, 82101364, 82271415, 82471422); National Key Research and Development Program of China (2023YFC2306502); Fundation of Jiangsu Province Research Hospital (YJXYY202204-ZD16, YJXYY202204-XKB12, YIXYY202204-ZD15)
Citations: cited by 1 paper (Europe PMC); 44 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Data availability

scRNA-seq data of mice brains are available in the Genome Sequence Archive database under accession number CRA033293. All data values reported in this work are reported in the Supporting Data Values file. The article and the supplemental material present all data needed to evaluate the conclusions.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Ziheng Wang (0000-0001-8873-732X); removed Ziheng Wang

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 6 keywords, 11 MeSH terms, 3 funders, 44 references.

Cite

This paper

Lu, Z., Shuai, Y., Wang, C., Liu, Z., Wang, Z., Liu, Q., Jiang, R., Zhu, J., Zhu, Y., Liao, W., Zhu, X., Zhao, J., Shi, K., Shi, W., & Gong, P. (2026). Aging-dependent microglial heterogeneity worsens outcomes in models of traumatic brain injury. The Journal of clinical investigation, 136(12), e196112. https://doi.org/10.1172/jci196112

BibTeX

@article{lu2026aging,
author = {Lu, Zhichao and Shuai, Yi and Wang, Chenxing and Liu, Zongheng and Wang, Ziheng and Liu, Qianqian and Jiang, Rui and Zhu, Jue and Zhu, Yongqi and Liao, Weiquan and Zhu, Xingjia and Zhao, Jingwei and Shi, Kaibin and Shi, Wei and Gong, Peipei},
title = {{Aging-dependent microglial heterogeneity worsens outcomes in models of traumatic brain injury}},
journal = {The Journal of clinical investigation},
year = {2026},
month = apr,
volume = {136},
number = {12},
pages = {e196112},
publisher = {American Society for Clinical Investigation},
issn = {0021-9738},
doi = {10.1172/jci196112},
url = {https://doi.org/10.1172/jci196112},
pmid = {41926211},
pmcid = {PMC13262727}
}

RIS

TY - JOUR
AU - Lu, Zhichao
AU - Shuai, Yi
AU - Wang, Chenxing
AU - Liu, Zongheng
AU - Wang, Ziheng
AU - Liu, Qianqian
AU - Jiang, Rui
AU - Zhu, Jue
AU - Zhu, Yongqi
AU - Liao, Weiquan
AU - Zhu, Xingjia
AU - Zhao, Jingwei
AU - Shi, Kaibin
AU - Shi, Wei
AU - Gong, Peipei
TI - Aging-dependent microglial heterogeneity worsens outcomes in models of traumatic brain injury
T2 - The Journal of clinical investigation
J2 - J Clin Invest
PY - 2026
DA - 2026/04/02
VL - 136
IS - 12
SP - e196112
SN - 0021-9738
PB - American Society for Clinical Investigation
DO - 10.1172/jci196112
UR - https://doi.org/10.1172/jci196112
LA - en
ER -

CSL-JSON

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