Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis
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...
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BMC
2025-08-01
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| Series: | Military Medical Research |
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| Online Access: | https://doi.org/10.1186/s40779-025-00631-1 |
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| author | Ze-Xi Jia Meng-Tian Guo Mei-Mei Li Pan Liao Bo Yan Wei Zhang Fang-Yuan Cheng Ya-Ru Liu Zi-Han Zhang Cheng Wei Jie Zhou Fang-Lian Chen Ping Lei Xin-Tong Ge |
| author_facet | Ze-Xi Jia Meng-Tian Guo Mei-Mei Li Pan Liao Bo Yan Wei Zhang Fang-Yuan Cheng Ya-Ru Liu Zi-Han Zhang Cheng Wei Jie Zhou Fang-Lian Chen Ping Lei Xin-Tong Ge |
| author_sort | Ze-Xi Jia |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3788334957cf465483bfeb64b0caccf9 |
| institution | Kabale University |
| issn | 2054-9369 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Military Medical Research |
| spelling | doaj-art-3788334957cf465483bfeb64b0caccf92025-08-20T03:42:23ZengBMCMilitary Medical Research2054-93692025-08-0112111810.1186/s40779-025-00631-1Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosisZe-Xi Jia0Meng-Tian Guo1Mei-Mei Li2Pan Liao3Bo Yan4Wei Zhang5Fang-Yuan Cheng6Ya-Ru Liu7Zi-Han Zhang8Cheng Wei9Jie Zhou10Fang-Lian Chen11Ping Lei12Xin-Tong Ge13Department of Geriatrics, Tianjin Medical University General HospitalDepartment of Internal Medicine, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Geriatrics, Tianjin Medical University General HospitalSchool of Medicine, Nankai UniversityDepartment of Geriatrics, Tianjin Medical University General HospitalDepartment of Geriatrics, Tianjin Medical University General HospitalDepartment of Geriatrics, Tianjin Medical University General HospitalDepartment of Geriatrics, Tianjin Medical University General HospitalSchool of Medicine, Nankai UniversityDepartment of Oncology-Pathology, Karolinska InstituteDepartment of Immunology, School of Basic Medical Sciences, Tianjin Medical UniversityTianjin Neurological Institute, Tianjin Medical University General HospitalDepartment of Geriatrics, Tianjin Medical University General HospitalDepartment of Geriatrics, Tianjin Medical University General HospitalAbstract 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.https://doi.org/10.1186/s40779-025-00631-1Repetitive mild traumatic brain injury (rmTBI)Interleukin-33 (IL-33)MicrogliaCognition |
| spellingShingle | Ze-Xi Jia Meng-Tian Guo Mei-Mei Li Pan Liao Bo Yan Wei Zhang Fang-Yuan Cheng Ya-Ru Liu Zi-Han Zhang Cheng Wei Jie Zhou Fang-Lian Chen Ping Lei Xin-Tong Ge Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis Military Medical Research Repetitive mild traumatic brain injury (rmTBI) Interleukin-33 (IL-33) Microglia Cognition |
| title | Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis |
| title_full | Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis |
| title_fullStr | Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis |
| title_full_unstemmed | Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis |
| title_short | Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis |
| title_sort | decreased il 33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis |
| topic | Repetitive mild traumatic brain injury (rmTBI) Interleukin-33 (IL-33) Microglia Cognition |
| url | https://doi.org/10.1186/s40779-025-00631-1 |
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