CD8+GZMK+CD27+CCR7+ T cells mobilized by splenic sympathetic nerves aggravate brain ischemia‒reperfusion injury via CCL19-positive endothelial cells
Splenic sympathetic activity critically modulates peripheral immunity after ischemic stroke, thus intervention in spleen sympathetic activity represents a promising therapeutic strategy for stroke. However, the mechanisms underlying spleen-brain-immune axis communication remain poorly understood. Here, we utilized a surgical denervation protocol to perform splenic sympathetic denervation (SDN), which significantly attenuated brain injury following stroke. Through single-cell RNA sequencing, we identified a novel GZMK<sup>+</sup>CD8<sup>+</sup>CD27<sup>+</sup>CCR7<sup>+</sup> T-cell subset in patients with acute ischemic stroke (AIS), which we designated stroke-associated T (Tsa) cells. The expansion of Tsa cells was positively correlated with the severity of clinical symptoms and was driven by the splenic sympathetic nervous system. Stroke-induced sympathetic activation triggers the release of splenic norepinephrine (NE), which preferentially signals through ADRB2 on Tsa cells to promote their mobilization. Additionally, ischemic injury induces endothelial cell-specific expression of CCL19, which chemoattracts Tsa cells into the brain parenchyma via their cognate CCR7 receptor, exacerbating neuroinflammatory injury and neurological deficits in a transient middle cerebral artery occlusion (tMCAO) mouse model. We developed a CCR7-targeting peptide to disrupt this chemotactic axis and reduce T-cell infiltration, thereby mitigating brain injury. Our findings highlight SDN as a promising therapeutic strategy to attenuate ischemia‒reperfusion injury and suggest its potential as an adjunctive therapy for reperfusion treatment in AIS patients.
Authors
- Shuo Leng (ORCID: https://orcid.org/0000-0003-0483-0557)
- Ying Bai (ORCID: https://orcid.org/0000-0002-5514-6280)
- Honghong Yao (ORCID: https://orcid.org/0000-0002-2128-0529)
- Shenyang Zhang
- Wei Jiang (ORCID: https://orcid.org/0000-0003-1591-4721)
- Lian Xu
- Bin Zheng (ORCID: https://orcid.org/0000-0002-7682-6648)
- Tianhao Zhu
- Yixin Jiang (ORCID: https://orcid.org/0009-0000-3823-9875)
- Daxing Li
- Bing Han (ORCID: https://orcid.org/0000-0001-8170-498X)
- Beicheng Zhang
- Mengqin Yuan (ORCID: https://orcid.org/0000-0002-3957-0727)
- Minzi Ju (ORCID: https://orcid.org/0009-0005-6541-9616)
- Zhi Wang (ORCID: https://orcid.org/0000-0002-5056-2242)
- John H. Zhang (ORCID: https://orcid.org/0000-0002-4319-4285)
- Yuan Zhang (ORCID: https://orcid.org/0000-0001-5914-2263)
- Yu Wang (ORCID: https://orcid.org/0000-0002-2065-8059)
- Ling Shen (ORCID: https://orcid.org/0000-0002-8801-3054)
- Hui Ren (ORCID: https://orcid.org/0000-0001-9864-5162)
- Xi Wen (ORCID: https://orcid.org/0009-0001-4301-3798)
- Xinchen Huo
Institutions
- Fujian Medical University (CN)
- Xuzhou Medical College (CN)
- Nantong University (CN)
- Loma Linda University (US)
- Southeast University (BD)
- Shanghai University of Traditional Chinese Medicine (CN)
- Zhongda Hospital Southeast University (CN)
- First Affiliated Hospital of Fujian Medical University (CN)
- Southeast University (CN)
- Nanjing Medical University (CN)
- Nanjing University of Aeronautics and Astronautics (CN)
Publication Details
- Journal
- Cellular and Molecular Immunology
- Published
- 2025-07-14
- DOI
- https://doi.org/10.1038/s41423-025-01311-9
- Citations
- 6
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.05
Funders
- Strong
- National Natural Science Foundation of China
- Government of Jiangsu Province
- National Science and Technology Major Project
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities