{
  "abstract": "Background: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) characterized by persistent neuroinflammation and immune cell infiltration. Despite extensive study, the specific mechanisms by which local microenvironmental signals enable peripheral immune cells to breach the blood-brain barrier (BBB)—especially without overt structural disruption—are not fully understood.\n\nMethods: We utilized integrated transcriptomic analysis to identify specific microglia populations in demyelinating lesions. In vitro cellular models, coupled with confocal microscopy and biochemical analyses, were employed to investigate the interaction between microglia-derived factors and vascular endothelial cells, specifically evaluating adhesion molecule dynamics and transendothelial migration. In vivo validation was performed using an experimental autoimmune encephalomyelitis (EAE) mouse model to assess the effects of targeted pharmacological inhibition on immune cell infiltration and clinical disease severity.\n\nResults: We identified a distinct MS-inflamed microglia (MIMS) population characterized by high expression of secreted phosphoprotein 1 (SPP1, osteopontin), which is markedly increased in chronic lesions. Integrated transcriptomic and in vitro experiments revealed that microglial SPP1 acts on endothelial cells via an interaction with the Integrin αVβ1 (ITGAV/ITGB1) receptor complex. Mechanistically, this engagement activates the Focal Adhesion Kinase (FAK)/NF-κB signaling cascade, driving the robust expression and dynamic turnover of endothelial adhesion molecules. Crucially, this SPP1-driven endothelial activation enables the massive, pan-lineage recruitment of circulating immune cells without evidence of overt barrier disruption. Furthermore, in vivo intrathecal inhibition of SPP1 significantly reduced peripheral immune cell migration into the CNS and alleviated disease severity in the EAE model.\n\nConclusions: CNS-resident microglia actively instruct the vascular endothelium via the SPP1-ITGAV-FAK axis to orchestrate peripheral immune cell entry without overt barrier disruption. These findings provide insights into neuro-immune crosstalk at the BBB and highlight a potential targetable pathway for modifying compartmentalized neuroinflammatory diseases.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08735-5.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000 China",
    "Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055 China",
    "Guangdong Provincial Key Laboratory of Hemoadsorption Technology, Guangzhou, 510700 China",
    "The Center of Mental and Neurological Disorders Study, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000 China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xia Xiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Shishi Shen"
    },
    {
      "affs": [
        0
      ],
      "name": "Tingting Cui"
    },
    {
      "affs": [
        0
      ],
      "name": "Hanzhang Tan"
    },
    {
      "affs": [
        0
      ],
      "name": "Shengfei Hu"
    },
    {
      "affs": [
        1
      ],
      "name": "Xia Deng"
    },
    {
      "affs": [
        0
      ],
      "name": "Yiying Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunping Cui"
    },
    {
      "affs": [
        2
      ],
      "name": "Boguang Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei Qiu"
    },
    {
      "affs": [
        1
      ],
      "name": "Liang Gao"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Yipeng Zhao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e8h4q12w9aeq8.bib",
  "cited_by": 0,
  "doi": "10.1186/s12967-026-08735-5",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712053/",
  "id": "e8h4q12w9aeq8",
  "issns": [
    "1479-5876"
  ],
  "landing_url": "https://doi.org/10.1186/s12967-026-08735-5",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2734|Multiple Sclerosis Research Studies"
    ]
  ],
  "openalex": "W7171628246",
  "pdf_url": null,
  "pmcid": "PMC13712053",
  "pmid": "42934676",
  "published": "2026-07-29",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/e8h4q12w9aeq8.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:43Z",
      "native_id": "PMC13712053",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12967-026-08735-5"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2734|Multiple Sclerosis Research Studies",
      "subfield": "general"
    }
  ],
  "title": "Blocking the microglia-endothelial axis via SPP1-ITGAV disruption attenuates neuroinflammation in multiple sclerosis",
  "title_text": "Blocking the microglia-endothelial axis via SPP1-ITGAV disruption attenuates neuroinflammation in multiple sclerosis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:43Z",
  "url": "https://research.draconitic.com/paper/e8h4q12w9aeq8",
  "venue": "Journal of Translational Medicine",
  "versions": []
}