The foam cell-derived exosomes exacerbate ischemic white matter injury via transmitting metabolic defects to microglia

Hang Zhang; Luo-Qi Zhou; Sheng Yang; Ming-Hao Dong; Lian Chen; Yi-Lin Lu; Lu-Yang Zhang; Lan Zhang; Yun-Hui Chu; Lu-Lu Xu; Xiao-Wei Pang; Li-Fang Zhu; Ting Xu; Tu-Ying Yong; Wei Wang; Dai-Shi Tian; Chuan Qin

doi:10.1016/j.cmet.2025.04.009

The foam cell-derived exosomes exacerbate ischemic white matter injury via transmitting metabolic defects to microglia

Cell Metab. 2025 May 3:S1550-4131(25)00219-0. doi: 10.1016/j.cmet.2025.04.009. Online ahead of print.

Authors

Hang Zhang¹, Luo-Qi Zhou¹, Sheng Yang¹, Ming-Hao Dong¹, Lian Chen¹, Yi-Lin Lu¹, Lu-Yang Zhang¹, Lan Zhang¹, Yun-Hui Chu¹, Lu-Lu Xu¹, Xiao-Wei Pang¹, Li-Fang Zhu¹, Ting Xu², Tu-Ying Yong³, Wei Wang⁴, Dai-Shi Tian⁵, Chuan Qin⁶

Affiliations

¹ Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Road, Guangzhou 510080, China.
³ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
⁴ Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: wwang@tjh.tjmu.edu.cn.
⁵ Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: tiands@tjh.tjmu.edu.cn.
⁶ Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: chuanqin@tjh.tjmu.edu.cn.

PMID: 40345179
DOI: 10.1016/j.cmet.2025.04.009

Abstract

Atherosclerosis (AS) has been shown to be an independent risk factor for vascular cognitive impairment (VCI), but the mechanisms remain unclear. Here, we found that AS circulating exosomes exacerbated ischemic white matter injury and VCI. Exosomes originating from macrophage-derived foam cells targeted microglia. Mechanistically, foam cell-derived exosomes transmitted redox imbalance, mitochondrial dysfunction, and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis. Anti-miR-101-3p or activation of Nrf2, both genetically and pharmacologically, could antagonize AS exosomes and ameliorate VCI. In conclusion, our findings reveal a distant connection between peripheral macrophages and brain microglia, which provides new insights and potential targets of AS-induced VCI.

Keywords: Nrf2; atherosclerosis; exosomes; foam cells; glucose metabolism; ischemic white matter injury; miR-101-3p; microglia; mitochondria.