Jia Ze-Xi, Guo Meng-Tian, Li Mei-Mei, Liao Pan, Yan Bo, Zhang Wei, Cheng Fang-Yuan, Liu Ya-Ru, Zhang Zi-Han, Wei Cheng, Zhou Jie, Chen Fang-Lian, Lei Ping, Ge Xin-Tong
Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Mil Med Res. 2025 Aug 5;12(1):46. doi: 10.1186/s40779-025-00631-1.
Repetitive mild traumatic brain injury (rmTBI) is a significant risk factor for neurodegeneration, characterized by pathological protein deposition and persistent neuroinflammation. Research has observed increased interleukin-33 (IL-33) levels in the peripheral blood of patients with rmTBI, suggesting IL-33 may participate in regulating the pathological development of rmTBI. The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI, and to explore its potential as a therapeutic target to improve the neurological outcome.
The study employed an rmTBI mouse model using the wild-type (WT) and IL-33 knockout mice. Cognitive function was assessed via the Y-maze and Barnes tests. The main cell type expressing IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), was then investigated in the mouse brain through immunofluorescence colocalization. As the primary neural cell responsible for ST2 expression, microglia were studied in vitro using the BV2 cell line. The effects of lipid droplets (LDs) accumulation and amyloid-beta (Aβ) phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells' phagocytosis. Additionally, HT22 neuronal apoptosis was assessed by flow cytometry. Finally, the cognitive effects of intranasal administration of IL-33 were evaluated in mice.
IL-33KO mice exhibited pronounced cognitive impairment after rmTBI. In the mouse brain, astrocytes were identified as the primary source of IL-33 secretion, while microglia predominantly expressed ST2. Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function. IL-33 mitigated LDs accumulation in BV2 cells and enhanced Aβ phagocytosis in vitro. In addition, the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage. Furthermore, intranasal administration of IL-33 was observed to be effective in alleviating neurodegeneration and cognitive outcome of rmTBI mice.
Dysfunction of the IL-33/ST2 axis following rmTBI leads to cognitive dysfunction via impairing microglial phagocytosis capacity and promoting neuronal damage. IL-33 would be a promising therapeutic target for alleviating neurodegeneration following rmTBI.
重复性轻度创伤性脑损伤（rmTBI）是神经退行性变的一个重要危险因素，其特征为病理性蛋白质沉积和持续性神经炎症。研究观察到rmTBI患者外周血中白细胞介素-33（IL-33）水平升高，提示IL-33可能参与调节rmTBI的病理发展。本研究旨在阐明IL-33在rmTBI后神经病理学进展中的作用及其机制，并探索其作为改善神经功能结局的治疗靶点的潜力。
本研究采用野生型（WT）和IL-33基因敲除小鼠建立rmTBI小鼠模型。通过Y迷宫和巴恩斯试验评估认知功能。然后通过免疫荧光共定位在小鼠脑中研究表达IL-33及其受体抑制肿瘤发生2（ST2）的主要细胞类型。作为负责ST2表达的主要神经细胞，使用BV2细胞系在体外研究小胶质细胞。测量脂滴（LDs）积累和淀粉样β蛋白（Aβ）吞噬作用的影响，以阐明IL-33对BV2细胞吞噬作用的影响。此外，通过流式细胞术评估HT22神经元凋亡。最后，评估鼻内给予IL-33对小鼠的认知影响。
rmTBI后IL-33基因敲除小鼠表现出明显的认知障碍。在小鼠脑中，星形胶质细胞被确定为IL-33分泌的主要来源，而小胶质细胞主要表达ST2。转录组测序显示IL-33显著影响吞噬功能。IL-33减轻了BV2细胞中LDs的积累，并在体外增强了Aβ吞噬作用。此外，激活IL-33/ST2信号的BV2细胞培养基减少了HT22神经元凋亡和轴突损伤。此外，观察到鼻内给予IL-33可有效减轻rmTBI小鼠的神经退行性变和改善认知结局。
rmTBI后IL-33/ST2轴功能障碍通过损害小胶质细胞吞噬能力和促进神经元损伤导致认知功能障碍。IL-33有望成为减轻rmTBI后神经退行性变的治疗靶点。
