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The foam cell-derived exosomal miRNA Novel-3 drives neuroinflammation and ferroptosis during ischemic stroke

Qin, Chuan, Dong, Ming-Hao, Tang, Yue, Chu, Yun-Hui, Zhou, Luo-Qi, Zhang, Hang, Yang, Sheng, Zhang, Lu-Yang, Pang, Xiao-Wei, Zhu, Li-Fang, Wang, Wei, Tian, Dai-Shi·2024·Nature Aging
DOI 10.1038/s43587-024-00727-8
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Abstract

Large artery atherosclerosis (LAA) is a prevalent cause of acute ischemic stroke (AIS). Understanding the mechanisms linking atherosclerosis to stroke is essential for developing appropriate intervention strategies. Here, we found that the exosomal miRNA Novel-3 is selectively upregulated in the plasma of patients with LAA-AIS. Notably, Novel-3 was predominantly expressed in macrophage-derived foam cells, and its expression correlated with atherosclerotic plaque vulnerability in patients undergoing carotid endarterectomy. Exploring the function of Novel-3 in a mouse model of cerebral ischemia, we found that Novel-3 exacerbated ischemic injury and targeted microglia and macrophages expressing ionized calcium-binding adapter molecule 1 in peri-infarct regions. Mechanistically, Novel-3 increased ferroptosis and neuroinflammation by interacting with striatin (STRN) and downregulating the phosphoinositide 3-kinase-AKT-mechanistic target of rapamycin signaling pathway. Blocking Novel-3 activity or overexpressing STRN provided neuroprotection under ischemic conditions. Our findings suggest that exosomal Novel-3, which is primarily derived from macrophage-derived foam cells, targets microglia and macrophages in the brain to induce neuroinflammation and could serve as a potential therapeutic target for patients with stroke who have atherosclerosis.

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Metadata

Authors
Qin, C., Dong, M.-H., Tang, Y., Chu, Y.-H., Zhou, L.-Q., Zhang, H., Yang, S., Zhang, L.-Y., Pang, X.-W., Zhu, L.-F., Wang, W., & Tian, D.-S.
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2024-10-28
Volume
4
Issue
12
Pages
1845-1861
ISSN
2662-8465
DOI
10.1038/s43587-024-00727-8
Cited by
38
References
2
Language
en
Licence
Funders
  • Ministry of Science and Technology of the People's Republic of China (2022ZD0204700)
  • National Natural Science Foundation of China (82271341, 82371404, 81873743)

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CoChat. (2026). Citation check: The foam cell-derived exosomal miRNA Novel-3 drives neuroinflammation and ferroptosis during ischemic stroke. https://app.cochat.ai/papers/10.1038/s43587-024-00727-8
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Qin, C., Dong, M.-H., Tang, Y., Chu, Y.-H., Zhou, L.-Q., Zhang, H., Yang, S., Zhang, L.-Y., Pang, X.-W., Zhu, L.-F., Wang, W., & Tian, D.-S. (2024). The foam cell-derived exosomal miRNA Novel-3 drives neuroinflammation and ferroptosis during ischemic stroke. Nature Aging. https://doi.org/10.1038/s43587-024-00727-8