Single-nucleus transcriptomics reveals sepsis-related neurovascular dysfunction in the human hippocampus.

Introduction: Sepsis is increasingly recognized as a major precipitant of long-term cognitive impairment, yet the cellular mechanisms underlying hippocampal vulnerability remain elusive.

Methods: We performed single-nucleus RNA sequencing of human hippocampal tissues from sepsis and control patients to profile neurovascular cell populations and their transcriptional changes.

Results: 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-microglia 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.

Discussion: These findings uncover a coordinated glial and vascular response to systemic inflammation, driven in part by dysfunctional astrocyte-microglia 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.