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  3. Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis

Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis

  • Mil Med Res. 2025 Aug 5;12(1):46. doi: 10.1186/s40779-025-00631-1.
Ze-Xi Jia # 1 2 3,  Meng-Tian Guo # 4,  Mei-Mei Li # 1 2 3,  Pan Liao 5,  Bo Yan 1 2 3,  Wei Zhang 1 2 3,  Fang-Yuan Cheng 1 2 3,  Ya-Ru Liu 1 2 3,  Zi-Han Zhang 5,  Cheng Wei 6,  Jie Zhou 7,  Fang-Lian Chen 8,  Ping Lei 9 10 11,  Xin-Tong Ge 12 13 14
Affiliations

Affiliations

  • 1 Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 2 Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 3 Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 4 Department of Internal Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100054, China.
  • 5 School of Medicine, Nankai University, Tianjin, 300071, China.
  • 6 Department of Oncology-Pathology, Karolinska Institute, 10339, Stockholm, Sweden.
  • 7 Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 8 Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. chenfanglian1976@tmu.edu.cn.
  • 9 Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, 300052, China. leiping1974@tmu.edu.cn.
  • 10 Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. leiping1974@tmu.edu.cn.
  • 11 Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. leiping1974@tmu.edu.cn.
  • 12 Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, 300052, China. xge@tmu.edu.cn.
  • 13 Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. xge@tmu.edu.cn.
  • 14 Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. xge@tmu.edu.cn.
  • # Contributed equally.
PMID: 40764944 DOI: 10.1186/s40779-025-00631-1
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Cognition; Interleukin-33 (IL-33); Microglia; Repetitive mild traumatic brain injury (rmTBI).

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