Regulatory T cell is critical for interleukin-33-mediated neuroprotection against stroke

Xinjing Liu; Ruiyao Hu; Lulu Pei; Pan Si; Chunhui Wang; Xuan Tian; Xiao Wang; Han Liu; Beng Wang; Zongping Xia; Yuming Xu; Bo Song

doi:10.1016/j.expneurol.2020.113233

Regulatory T cell is critical for interleukin-33-mediated neuroprotection against stroke

Exp Neurol. 2020 Jun:328:113233. doi: 10.1016/j.expneurol.2020.113233. Epub 2020 Feb 7.

Authors

Xinjing Liu¹, Ruiyao Hu¹, Lulu Pei¹, Pan Si¹, Chunhui Wang¹, Xuan Tian¹, Xiao Wang¹, Han Liu¹, Beng Wang¹, Zongping Xia², Yuming Xu³, Bo Song⁴

Affiliations

¹ Department of Neurology, the First Affiliated Hospital of Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China; The Henan Key Laboratory of Cerebrovascular Disease, Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China.
² The Henan Key Laboratory of Cerebrovascular Disease, Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China; Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China.
³ Department of Neurology, the First Affiliated Hospital of Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China; The Henan Key Laboratory of Cerebrovascular Disease, Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China. Electronic address: xuyuming@zzu.edu.cn.
⁴ Department of Neurology, the First Affiliated Hospital of Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China; The Henan Key Laboratory of Cerebrovascular Disease, Zhengzhou University, No.1 Eastern Jianshe Road, Zhengzhou 450052, Henan, China. Electronic address: ffcsongb@zzu.edu.cn.

PMID: 32044328
DOI: 10.1016/j.expneurol.2020.113233

Abstract

Interleukin-33 (IL-33) is known to activate the regulatory T lymphocytes (Tregs), which are negatively correlated with brain damage after ischemic stroke. In this study, we aimed to investigate the role of Tregs in IL-33-mediated neuroprotection and elucidate the underlying mechanisms. In vivo, male C57BL/6 N mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO), followed by daily administration of vehicle or IL-33 immediately after injury. Tregs were depleted by intraperitoneal administration of anti-CD25 antibody (anti-CD25Ab). Behavioral changes, brain edema, neuronal injury, Treg percentages, and cytokine expression levels were investigated in each group. In vitro experiments, primary mouse neuronal cells were subjected to oxygen-glucose deprivation (OGD) for 3 h. Vehicle- or drug-conditioned Tregs were applied to the neurons at the time of induction of hypoxia. Neuronal apoptosis and cytokine expression were measured in each group. The results indicate that intraperitoneal administration of anti-CD25Ab reduced CD4 + CD25 + Foxp3+ Tregs, increased infarct volume, enhanced stroke-induced cell death, and decreased sensorimotor functions. Notably, IL-33 increased CD4 + CD25 + Foxp3+ Tregs in the spleen and brain. However, blockading ST2 attenuated these effects of IL-33. The supernatant of the IL-33-treated Treg culture reduced neuronal apoptosis and elevated the production of the Treg cytokines IL-10, IL-35, and transforming growth factor-β (TGF-β). Anti-CD25Ab abrogated the neuroprotective effect of IL-33. Mechanistically, the neuroprotective effects of IL-33 were associated with reduction in apoptosis-related proteins and production of Tregs related cytokines. Overall, these findings showed that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation via a mechanism involving anti-apoptosis proteins and cytokines, representing a promising immune modulatory target for the treatment of stroke.

Keywords: Cerebral ischemia; Interleukin-33; Neuroprotection; Regulatory T cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Interleukin-33 / immunology*
Lymphocyte Activation / immunology
Male
Mice
Mice, Inbred C57BL
Neuroprotection / immunology*
Stroke / immunology*
Stroke / pathology
T-Lymphocytes, Regulatory / immunology*

Substances

Il33 protein, mouse
Interleukin-33