Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery

Xiaotao Zhang, Huaming Li, Yichen Gu, An Ping, Jiarui Chen, Qia Zhang, Zhouhan Xu, Junjie Wang, Shenjie Tang, Rui Wang, Jianan Lu, Lingxiao Lu, Chenghao Jin, Ziyang Jin, Jianmin Zhang () and Ligen Shi ()
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Xiaotao Zhang: Zhejiang University
Huaming Li: Zhejiang University
Yichen Gu: Zhejiang University
An Ping: Zhejiang University
Jiarui Chen: Zhejiang University
Qia Zhang: Zhejiang University
Zhouhan Xu: Zhejiang University
Junjie Wang: Zhejiang University
Shenjie Tang: Zhejiang University
Rui Wang: Zhejiang University
Jianan Lu: Zhejiang University
Lingxiao Lu: Zhejiang University
Chenghao Jin: Zhejiang University
Ziyang Jin: Zhejiang University
Jianmin Zhang: Zhejiang University
Ligen Shi: Zhejiang University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral immune cells compete with resident microglia for spatial niches in the brain, but how modulating this balance affects recovery remains unclear. Here, we use PLX5622 to create spatial niches for peripheral immune cells, altering the competition between infiltrating immune cells and resident microglia in male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase microglia attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) with reparative properties, characterized by high expression of GPNMB and CD63, enhanced lipid metabolism, and pro-angiogenic activity. Transplantation of RAMf into stroke-affected mice improves white matter integrity and vascular repair. We identify Mafb as the transcription factor regulating the reparative phenotype of RAMf. These findings highlight strategies to optimize immune cell dynamics for post-stroke rehabilitation.

Date: 2025
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DOI: 10.1038/s41467-025-58254-y

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