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Updated: Jan 14, 2026
A Preclinical Controlled Cortical Impact Model for Traumatic Hemorrhage Contusion and Neuroinflammation
Published on: June 10, 2020
IL-25-ILC2-IL-13 axis improves traumatic brain injury by mediating CXCL-10-dependent regulation of blood brain
Min Peng1, Daoxing Shu1, Zheng Chen1
1The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241001, People's Republic Of China.
Background:
Traumatic brain injury (TBI) causes severe disruption of the blood-brain barrier (BBB), a key event that contributes to secondary neurological damage. Interleukin-25 (IL-25) has recently emerged as an important regulator of neuroinflammation, yet its role in BBB repair after TBI remains unclear. This study investigated the protective effects of IL-25 on BBB integrity and neurological function in mice following TBI and explored the underlying mechanisms.
Methods:
IL-25 expression in mouse serum and cortical tissue after TBI was quantified using enzyme-linked immunosorbent assays, and its cellular sources were identified via immunofluorescence staining. The impact of exogenous IL-25 on BBB integrity was evaluated by measuring, tight junction proteins (ZO-1, occludin, and claudin-5), Evans Blue extravasation, and cerebral edema on magnetic resonance imaging. Mechanistic, investigations using flow cytometry and in vitro oxygen glucose deprivation/reoxygenation models assessed whether IL-25 acted directly on brain microvascular endothelial cells (BMECs) or indirectly through immune pathways. Cytokine array and Western blot analyses were used to identify downstream mediators, and single-cell RNA sequencing was performed to characterize IL-25-induced transcriptional changes. Neurological function was assessed using the modified Neurological Severity Score, rotarod test, and Morris water maze.
Results:
IL-25 levels increased significantly in the cortex and serum after TBI, peaking at day 3, with neurons and BMECs identified as the main sources. Exogenous IL-25 administration alleviated BBB dysfunction, restored tight junction protein expression, reduced Evans Blue leakage, and diminished cerebral edema. Mechanistically, IL-25 acted indirectly by activating brain-resident group 2 innate lymphoid cells to secrete interleukin-13 (IL-13), rather than acting directly on BMECs. IL-13 preserved BBB integrity by suppressing C-X-C motif chemokine ligand 10 (CXCL-10) expression and inhibiting endothelial pyroptosis. Single-cell RNA sequencing confirmed upregulation of BBB-protective genes such as Tiam1, Hsp90aa1, and Hes1, along with activation of tight junction and transforming growth factor-β signaling pathways. IL-25 treatment improved both motor coordination and cognitive performance after TBI.
Conclusions:
IL-25 promotes BBB repair and enhances neurological recovery following TBI by inducing ILC2-derived IL-13, which suppresses CXCL-10 and endothelial pyroptosis. These findings identify IL-25 as a potential therapeutic target for mitigating BBB damage and improving outcomes after TBI.
