IL-33/ST2 Axis Protects Against Traumatic Brain Injury Through Enhancing the Function of Regulatory T Cells.
IL-33/ST2 Axis Protects Against Traumatic Brain Injury Through Enhancing the Function of Regulatory T Cells.
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DOI：
10.3389/fimmu.2022.860772
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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创伤性脑损伤（TBI）因其对神经功能的长期后遗症而成为一种毁灭性的疾病。 TBI 后的炎症反应对于损伤扩展和修复至关重要。最近对中枢神经系统 (CNS) 疾病的研究揭示了 IL-33 及其受体 (ST2) 作为警报系统启动免疫反应的重要性。本研究探讨了 IL-33/ST2 信号传导在 TBI 中的作用。使用受控皮质冲击 (CCI) 模型在成年雄性 C57BL/6J 小鼠中诱导 TBI。我们发现，TBI 后早期，受伤的大脑和血液中 IL-33 的表达增加，循环和浸润性调节性 T 细胞 (Treg) 中的 ST2 升高。 TBI 后 5 天，ST2 缺陷小鼠的血液和大脑中 Treg 数量减少。 ST2敲除小鼠脑损伤面积扩大，并伴有TBI后5天感觉运动功能恶化。相比之下，TBI 后使用 IL-33（2 μg/30 g 体重，鼻内）治疗 3 天可显着缩小脑损伤大小，并在 TBI 后 5 天改善神经功能。同时，IL-33 治疗增加了循环和脑浸润性 Tregs 中 ST2 的表达。为了进一步探讨 Tregs 在 IL-33/ST2 介导的神经保护中的参与，通过注射 CD25 抗体来耗尽 Tregs。 Tregs 的缺失显着降低了 TBI 后 IL-33 的保护作用。体外研究证实，IL-33 (50 ng/ml) 增加了激活的 Tregs 中 IL-10 和 TGFβ 的产生，并增强了 Tregs 对效应 T 细胞增殖的抑制作用。总而言之，这项研究表明，IL-33/ST2 信号传导的激活至少部分是通过调节 Treg 反应来减少脑损伤大小并减轻 TBI 后的功能缺陷。 IL-33 可能代表一种改善 TBI 结局的新免疫治疗策略。
Traumatic brain injury (TBI) is a devastating condition due to its long-term sequelae on neurological functions. Inflammatory responses after TBI are critical for injury expansion and repair. Recent research in central nervous system (CNS) disorders reveals the importance of IL-33 and its receptor (ST2) as an alarmin system to initiate immune responses. This study explored the role of IL-33/ST2 signaling in TBI. TBI was induced in adult male C57BL/6J mice using a controlled cortical impact (CCI) model. We found that the expression of IL-33 increased in the injured brain and blood, and ST2 was elevated in the circulating and infiltrating regulatory T cells (Tregs) early after TBI. ST2 deficient mice exhibited reduced Treg numbers in the blood and brain 5 days after TBI. The brain lesion size was enlarged in ST2 knockout mice, which was accompanied by deteriorated sensorimotor function 5 days after TBI. In contrast, post-TBI treatment with IL-33 (2 μg/30 g body weight, intranasal) for 3 days significantly reduced brain lesion size and improved neurological functions 5 days after TBI. Meanwhile, IL-33 treatment increased ST2 expression in circulating and brain infiltrating Tregs. To further explore the involvement of Tregs in IL-33/ST2-mediated neuroprotection, Tregs were depleted by CD25 antibody injection. The absence of Tregs significantly reduced the protective effect of IL-33 after TBI. In vitro study confirmed that IL-33 (50 ng/ml) increased the production of IL-10 and TGFβ from activated Tregs and boosted the inhibitory effect of Tregs on T effector cell proliferation. Taken together, this study suggests that the activation of IL-33/ST2 signaling reduces brain lesion size and alleviates functional deficits after TBI at least partially through regulating the Treg response. IL-33 may represent a new immune therapeutic strategy to improve TBI outcomes.