调节性 T 细胞通过抑制 STAT3 减轻小胶质细胞炎症，促进脊髓损伤后的功能恢复。

Regulatory T cells promote functional recovery after spinal cord injury by alleviating microglia inflammation via STAT3 inhibition.

机构信息

Department of Neurology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.

Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China.

出版信息

CNS Neurosci Ther. 2023 Aug;29(8):2129-2144. doi: 10.1111/cns.14161. Epub 2023 Mar 13.

BACKGROUND

Immediately after spinal trauma, immune cells, and proinflammatory cytokines infiltrate the spinal cord and disrupt the focal microenvironment, which impedes axon regeneration and functional recovery. Previous studies have reported that regulatory T cells (Tregs) enter the central nervous system and exert immunosuppressive effects on microglia during multiple sclerosis and stroke. However, whether and how Tregs interact with microglia and modulate injured microenvironments after spinal cord injury (SCI) remains unknown.

METHOD

Regulatory T cells spatiotemporal characteristics were analyzed in a mouse contusion SCI model. Microglia activation status was evaluated by immunostaining and RNA sequencing. Cytokine production in injured spinal cord was examined using Luminex. The role of STAT3 in Treg-microglia crosstalk was investigated in a transwell system with isolated Tregs and primary microglia.

RESULTS

Regulatory T cells infiltration of the spinal cord peaked on day 7 after SCI. Treg depletion promoted microglia switch to a proinflammatory phenotype. Inflammation-related genes, such as ApoD, as well as downstream cytokines IL-6 and TNF-α were upregulated in microglia in Treg-depleted mice. STAT3 inhibition was involved in Treg-microglia crosstalk, and STAT3 chemical blockade improved function recovery in Treg-depleted mice.

CONCLUSION

Our results suggest that Tregs promote functional recovery after SCI by alleviating microglia inflammatory reaction via STAT3.

背景

脊髓损伤后，免疫细胞和促炎细胞因子立即浸润脊髓，破坏局部微环境，阻碍轴突再生和功能恢复。先前的研究报道，调节性 T 细胞（Tregs）在多发性硬化症和中风期间进入中枢神经系统，并对小胶质细胞发挥免疫抑制作用。然而，Tregs 是否以及如何与小胶质细胞相互作用并调节脊髓损伤（SCI）后的损伤微环境尚不清楚。

方法

在小鼠挫伤 SCI 模型中分析调节性 T 细胞的时空特征。通过免疫染色和 RNA 测序评估小胶质细胞激活状态。使用 Luminex 检测损伤脊髓中的细胞因子产生。在离体 Tregs 和原代小胶质细胞的 Transwell 系统中研究 STAT3 在 Treg-小胶质细胞相互作用中的作用。

结果

SCI 后第 7 天，调节性 T 细胞浸润脊髓达到峰值。Treg 耗竭促进小胶质细胞向促炎表型转化。在 Treg 耗竭小鼠的小胶质细胞中，炎症相关基因，如 ApoD 以及下游细胞因子 IL-6 和 TNF-α 上调。STAT3 抑制参与 Treg-小胶质细胞相互作用，STAT3 化学阻断可改善 Treg 耗竭小鼠的功能恢复。