Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

Xiaotao Zhang; Rui Wang; Haoran Chen; Chenghao Jin; Ziyang Jin; Jianan Lu; Liang Xu; Yunrong Lu; Jianmin Zhang; Ligen Shi

doi:10.1186/s12979-022-00289-6

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

Immun Ageing. 2022 Jul 25;19(1):34. doi: 10.1186/s12979-022-00289-6.

Authors

Xiaotao Zhang^{1

2}, Rui Wang^{1

2}, Haoran Chen¹, Chenghao Jin^{1

2}, Ziyang Jin^{1

2}, Jianan Lu^{1

2}, Liang Xu^{1

2}, Yunrong Lu³, Jianmin Zhang^{4

5

6

7}, Ligen Shi^{8

9}

Affiliations

¹ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
² Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, China.
³ Department of Psychiatry, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁴ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. zjm135@zju.edu.cn.
⁵ Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, China. zjm135@zju.edu.cn.
⁶ Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China. zjm135@zju.edu.cn.
⁷ Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China. zjm135@zju.edu.cn.
⁸ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. slg0904@zju.edu.cn.
⁹ Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, China. slg0904@zju.edu.cn.

Abstract

Background: The immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear.

Results: Chronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8⁺ memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly.

Conclusions: Our research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

Keywords: Aging; Blood–brain barrier; Endothelial cells; Microglia; Single-cell transcriptome; T cells.