Astrocyte-derived HMGB1 compromises the integrity of the blood-brain barrier through the CaM/CaMKII/AQP4 pathway and the protective function of trifluoperazine.

Overview

1. Key Laboratory of Exploitation and Study of Distinctive Plants of Sichuan Provincial Education Department, Sichuan University of Arts and Science, Dazhou, China
2. State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
3. Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Hubei Jiangxia Laboratory, Wuhan, Hubei, China
4. Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People’s Republic of China, Wuhan, Hubei, China
5. International Research Centre for Animal Disease, Ministry of Science and Technology of the People’s Republic of China, Wuhan, Hubei, China
6. Dazhou Traditional Chinese Medicine (TCM) Research and Development Centre (R&D), Dazhou, China
7. Dazhou TCM Industry Incubation Center, Dazhou, China

Abstract

The integrity of the blood–brain barrier (BBB) is crucial for maintaining the function and homeostasis of the central nervous system (CNS), with astrocytes playing a key role in this process. Our study found that infection with the Japanese encephalitis virus (JEV) promoted the translocation of high-mobility group box 1 (HMGB1) from the nucleus to the extracellular space of astrocytes, a process directly associated with BBB disruption. Through bioinformatics analysis, we identified potential targets of encephalitis and constructed a protein–protein interaction (PPI) network. Subsequent functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, highlighted the calcium signaling pathway as an important regulatory mechanism. Evidence from our in vitro and in vivo model experiments showed that HMGB1 can induce the increase of calcium ions (Ca²+) in astrocytes, thereby activating the calcium signaling pathway and promoting the translocation of aquaporin-4 (AQP4) to the plasma membrane, ultimately leading to BBB disruption. We also performed molecular docking and molecular dynamics simulations to determine the binding affinity between trifluoperazine (TFP) and calmodulin (CaM). TFP binds to CaM and blocks the translocation of AQP4 to the plasma membrane, thereby alleviating HMGB1-mediated BBB disruption. Overall, our data indicate that TFP protects BBB integrity through the CaM–CaMKII–AQP4 axis and identifies this pathway as a promising therapeutic target for the clinical treatment of Japanese encephalitis and other central nervous system diseases.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE154002, at NCBI GEO; found in “Data availability statement”

Data availability statement

The dataset analyzed in this study is publicly available in the NCBI Gene Expression Omnibus (GEO) repository under accession number GSE154002 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154002). The permanent direct access URL is: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154002. All other data supporting the findings of this study are included within the article and its Supplementary Materials.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 3 authors, 5 keywords, 14 MeSH terms, 56 references.

Cite

This paper

Zou, S.-S., Chen, L.-L., & Cui, M. (2026). Astrocyte-derived HMGB1 compromises the integrity of the blood-brain barrier through the CaM/CaMKII/AQP4 pathway and the protective function of trifluoperazine. Frontiers in immunology, 17, 1852083. https://doi.org/10.3389/fimmu.2026.1852083

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