The department of Endocrinology, Renhe Hospital of China Three Gorges University, Yichang City, Hubei Province, China.
The Department of Neurology, Renhe Hospital of China Three Gorges University, Yichang City, Hubei Province, China.
Immunol Invest. 2023 Nov;52(4):482-498. doi: 10.1080/08820139.2023.2197009. Epub 2023 Apr 19.
Regulatory T cells (Tregs) play a remarkable role in modulating post-ischemic neuroinflammation. However, the characteristics of Tregs in diabetic ischemic stroke remain unknown.
Transient middle cerebral artery occlusion (MCAO) was conducted on leptin receptor-mutated db/db mice and db/+ mice. The number, cytokine production, and signaling features of Tregs in peripheral blood and ipsilateral hemispheres were evaluated by flow cytometry. Treg plasticity was assessed by the adoptive transfer of splenic Tregs into mice. The effect of ipsilateral macrophages/microglia on Treg plasticity was determined by co-culture analysis.
db/db mice had more infiltrating Tregs in their ipsilateral hemispheres than db/+ mice. Infiltrating Tregs in db/db mice expressed higher transforming growth factor-β (TGF-β), interleukin-10 (IL-10), forkhead box P3 (Foxp3), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and T-box expressed in T cells (T-bet) in comparison to infiltrating Tregs in db/+ mice, suggesting promoted generation of T helper 1 (Th1)-like Tregs in the brains of db/db mice after stroke. The post-ischemic brain microenvironment of db/db mice significantly up-regulated IFN-γ, TNF-α, T-bet, IL-10, and TGF-β in infiltrating Tregs. Moreover, ipsilateral macrophages/microglia remarkably enhanced the expression of IFN-γ, TNF-α, and T-bet but not IL-10 and TGF-β in Tregs. db/db macrophages/microglia were more potent in up-regulating IFN-γ, TNF-α, and T-bet than db/+ macrophages/microglia. Interleukin-12 (IL-12) blockage partially abolished the modulatory effect of macrophages/microglia on Tregs.
The generation of Th1-like Tregs was promoted in the brains of type 2 diabetic mice after stroke. Our study reveals significant Treg plasticity in diabetic stroke. Foxp3: forkhead box P3; IFN-γ: interferon-γ; IL-10: interleukin-10; IL-12: interleukin-12; MCAO: middle cerebral artery occlusion; PBS: phosphate-buffered saline; STAT1: Signal transducer and activator of transcription 1; STAT5: Signal transducer and activator of transcription 1; T-bet: T-box expressed in T cells; TGF-β: transforming growth factor-β; Th1: T helper 1; TNF-α: tumor necrosis factor-α; Tregs: regulatory T cells. Foxp3: forkhead box P3; IFN-γ: interferon-γ; IL-10: interleukin-10; IL-12: interleukin-12; MCAO: middle cerebral artery occlusion; PBS: phosphate-buffered saline; STAT1: Signal transducer and activator of transcription 1; STAT5: Signal transducer and activator of transcription 1; T-bet: T-box expressed in T cells; TGF-β: transforming growth factor-β; Th1: T helper 1; TNF-α: tumor necrosis factor-α; Tregs: regulatory T cells.
调节性 T 细胞（Tregs）在调节缺血后神经炎症方面发挥着显著作用。然而，糖尿病缺血性中风患者 Tregs 的特征尚不清楚。
对瘦素受体突变型 db/db 小鼠和 db/+ 小鼠进行短暂性大脑中动脉闭塞（MCAO）。通过流式细胞术评估外周血和同侧半球中 Tregs 的数量、细胞因子产生和信号特征。通过脾 Tregs 的过继转移评估 Treg 可塑性。通过共培养分析确定同侧巨噬细胞/小胶质细胞对 Treg 可塑性的影响。
db/db 小鼠同侧半球浸润的 Tregs 数量多于 db/+ 小鼠。与 db/+ 小鼠相比，db/db 小鼠的浸润 Tregs 表达更高水平的转化生长因子-β（TGF-β）、白细胞介素-10（IL-10）、叉头框 P3（Foxp3）、干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）和 T 细胞中表达的 T 框（T-bet），提示 db/db 小鼠中风后大脑中 Th1 样 Tregs 的生成增加。db/db 小鼠的缺血后脑微环境显著上调了浸润 Tregs 中的 IFN-γ、TNF-α、T-bet、IL-10 和 TGF-β。此外，同侧巨噬细胞/小胶质细胞显著增强了 Tregs 中 IFN-γ、TNF-α和 T-bet 的表达，但不增强 IL-10 和 TGF-β 的表达。db/db 巨噬细胞/小胶质细胞在上调 IFN-γ、TNF-α和 T-bet 方面比 db/+ 巨噬细胞/小胶质细胞更有效。白细胞介素-12（IL-12）阻断部分消除了巨噬细胞/小胶质细胞对 Tregs 的调节作用。
2 型糖尿病小鼠中风后大脑中 Th1 样 Tregs 的生成增加。我们的研究揭示了糖尿病中风中 Treg 的显著可塑性。Foxp3：叉头框 P3；IFN-γ：干扰素-γ；IL-10：白细胞介素-10；IL-12：白细胞介素-12；MCAO：大脑中动脉闭塞；PBS：磷酸盐缓冲盐水；STAT1：信号转导和转录激活因子 1；STAT5：信号转导和转录激活因子 1；T-bet：T 细胞中表达的 T 盒；TGF-β：转化生长因子-β；Th1：辅助性 T 细胞 1；TNF-α：肿瘤坏死因子-α；Tregs：调节性 T 细胞。Foxp3：叉头框 P3；IFN-γ：干扰素-γ；IL-10：白细胞介素-10；IL-12：白细胞介素-12；MCAO：大脑中动脉闭塞；PBS：磷酸盐缓冲盐水；STAT1：信号转导和转录激活因子 1；STAT5：信号转导和转录激活因子 1；T-bet：T 细胞中表达的 T 盒；TGF-β：转化生长因子-β；Th1：辅助性 T 细胞 1；TNF-α：肿瘤坏死因子-α；Tregs：调节性 T 细胞。
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