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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Sepsis is increasingly recognized as a major precipitant of long-term cognitive impairment, yet the cellular mechanisms underlying hippocampal vulnerability remain elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed single-nucleus RNA sequencing of human hippocampal tissues from sepsis and control patients to profile neurovascular cell populations and their transcriptional changes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified profound neurovascular alterations involving 21 distinct cell populations. Astrocytes and microglia exhibited marked polarization: Astrocyte 2 showed simultaneous upregulation of neurotoxic A1 and neuroprotective A2 gene signatures in sepsis, whereas Astrocyte 1 displayed reduced A1 activity and a relatively quiescent profile. Microglia 2 demonstrated a prominent M1-like inflammatory signature, including elevated HLA-DRA, IL1B, and TNF, while Microglia 1 downregulated both M1 and M2 markers, suggesting a hypo-responsive state. Intercellular communication analysis revealed intensified astrocyte\u2013microglia interactions in the septic hippocampus. Endothelial and mural cells exhibited transcriptional signatures of blood-brain barrier disruption, oxidative stress, and compromised vascular homeostasis. Key molecular pathways associated with antigen presentation, cytokine signaling, and vascular permeability were selectively activated across neurovascular compartments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings uncover a coordinated glial and vascular response to systemic inflammation, driven in part by dysfunctional astrocyte\u2013microglia crosstalk and pro-inflammatory polarization. Such changes may underlie blood-brain barrier breakdown and contribute to sustained neuroinflammation and cognitive decline in sepsis survivors. Targeting glial-vascular signaling axes and modulating astrocyte or microglial polarization states may offer promising avenues for therapeutic intervention in post-sepsis neurological sequelae.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1648278","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T04:13:33Z","timestamp":1757909613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Single-nucleus transcriptomics reveals sepsis-related neurovascular dysfunction in the human hippocampus"],"prefix":"10.3389","volume":"16","author":[{"given":"Liu","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent 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