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The IL-25–ILC2–IL-13 axis improves traumatic brain injury by mediating CXCL-10-dependent regulation of Blood Brain Barrier integrity

ABSTRACT: Traumatic brain injury (TBI) induces severe disruption of the blood brain barrier (BBB), a pivotal event that drives secondary neurological damage. Interleukin-25 (IL-25) has emerged as a key modulator of neuroinflammation, but its role and underlying mechanisms in BBB repair after TBI remain unclear. Here, we investigated the protective effects of IL-25 on BBB integrity and neurological function in mice following TBI. Using enzyme-linked immunosorbent assay, we found that IL-25 levels in brain tissue and serum were significantly elevated after TBI, peaking at day 3, with brain microvascular endothelial cells (BMECs) identified as the primary source through immunofluorescence staining. Exogenous IL-25 administration ameliorated BBB dysfunction, as shown by restored expression of tight junction proteins (ZO-1, occludin, claudin-5), reduced Evans Blue extravasation, and decreased cerebral edema on magnetic resonance imaging. Mechanistically, flow cytometry and in vitro oxygen glucose deprivation/reoxygenation models revealed that IL-25 exerted its effects indirectly by activating brain-resident group 2 innate lymphoid cells to secrete interleukin-13 (IL-13), rather than acting directly on BMECs. Cytokine array and Western blot analyses demonstrated that IL-13 preserved BBB integrity by suppressing C-X-C motif chemokine ligand 10 (CXCL-10) expression and inhibiting endothelial cell pyroptosis. Single-cell RNA sequencing further confirmed that IL-25 upregulated BBB-protective genes (e.g., tiam1, hsp90aa1) and activated tight junction and transforming growth factor-beta signaling pathways. Behaviorally, IL-25 treatment improved motor coordination (modified Neurological Severity Score, rotarod test) and cognitive performance (Morris water maze) after TBI. Collectively, our findings indicate that IL-25 promotes BBB repair and neurological recovery after TBI by activating ILC2-derived IL-13, which suppresses CXCL-10 and endothelial pyroptosis. This study highlights IL-25 as a promising therapeutic target for TBI-induced BBB disruption.

ORGANISM(S): Mus musculus

PROVIDER: GSE308368 | GEO | 2026/02/18

REPOSITORIES: GEO

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Project description:Next-generation sequencing (NGS) has significantly facilitated the analysis of the gene profile and elucidated the molecular mechanisms important for specific cell lineage differentiated from human pluripotent stem cells (hPSCs). Here we report the application of RNA-sequencing technology for transcriptome profile of primary human brain microvascular endothelial cells (BMECs) and hPSC-derived BMECs, and comparison of transcriptomes among cells, including hPSCs, mesodermal progenitors, ectodermal progenitors, endodermal progenitors, hBMECs and hPSC-derived BMECs from hPSCs. Four different BMEC samples differentiated from hPSCs by two different methods and hBMECs were performed in IIIumina HiSeq2500. The resulting sequence reads (about 20 million reads per sample) were mapped to human genome (hg19) using HISAT, and the RefSeq transcript levels (FPKMs) were quantified using the python script rpkmforgenes.py. We next analyzed the expression of a subset of genes that regulate key BBB attributes, including tight junctions and molecular transporters. The gene set comprises 20 tight junction-related genes and an unbiased list of all 25 CLDN genes, all 407 solute carrier (SLC) transporters, and all 53 ATP-binding cassette (ABC) transporters regardless of prior knowledge of BBB association. Primary human BMECs expressed 234 of these genes. BMECs differentiated from hPSCs via the defined method expressed many of these same genes (206 of 234 (88%)) as did BMECs differentiated via the UM method (208 of 234 (89%), indicating a close similarity between hPSC-derived BMECs and primary human BMECs with respect to transcripts having likely relevance to BBB function. RNA sequencing was used to compare global gene expression profiles in the hPSC-derived BMECs with BMECs generated from our previously reported co-differentiation system and primary human BMECs. As expected, hPSC-derived BMECs from three independent differentiations clustered closely and were similar to those generated from the undefined UM platform. Moreover, the hPSC-derived BMECs clustered with primary human BMECs and were distinct from undifferentiated hPSCs and hPSC-derived ectoderm, endoderm and mesodermThis study provides detailed transcriptome comparison between hBMECs and hPSC-derived BMECs and unveils important genes related BMEC phenotypes.

Project description:Background: Emerging evidence suggests that chronic stress compromises blood‒brain barrier (BBB) integrity by disrupting brain microvascular endothelial cells (BMECs), contributing to the development of cognitive impairments. Thus, targeting the BBB is expected to be a promising treatment strategy. The biological function of rutin has been investigated in neurological disorders; however, its regulatory role in stress-induced BBB damage and cognitive decline and the underlying mechanisms remain elusive. Methods: In a chronic unpredictable mild stress (CUMS) mouse model, a fluorescent dye assay and behavioral tests, including a novel object recognition test and Morris water maze, were performed to evaluate the protective effects of rutin on BBB integrity and cognition. The effects of rutin on BMEC function were also investigated in hCMEC/D3 cells (a human brain microvascular endothelial cell line) in vitro. Furthermore, the molecular mechanisms by which rutin restores BBB endothelium dysfunction were explored via RNA-seq, quantitative real-time PCR, western blotting, immunofluorescence and chromatin immunoprecipitation. Finally, biotinylated tumor necrosis factor-α (TNF-α) was employed to test the influence of rutin on the ability of circulating TNF-α to cross the BBB. Results: We identified that rutin attenuated BBB hyperpermeability and cognitive impairment caused by the 8-week CUMS procedure. Moreover, rutin promoted the proliferation, migration and angiogenesis ability of BMECs through positively regulating the expression of genes involved. Furthermore, rutin impeded histone deacetylase 1 (HDAC1) recruitment and stabilized H3K27ac to increase Claudin-5 protein levels. Ultimately, normalization of the hippocampal HDAC1‒Claudin-5 axis by rutin blocked the infiltration of circulating TNF-α into the brain parenchyma and alleviated neuroinflammation. Conclusions: This work establishes a protective role of rutin in regulating BMEC function and BBB integrity and reveals that rutin is a potential drug candidate for curing chronic stress-induced cognitive deficits.

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The IL-25–ILC2–IL-13 axis improves traumatic brain injury by mediating CXCL-10-dependent regulation of Blood Brain Barrier integrity

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