Coordinated response of vascular and glial cells in a pig model of sepsis

This snRNAseq analysis revealed dramatic alterations in vascular cell populations, accompanied by concomitant glial cell activation. Surprisingly minimal changes were noted in neurons, likely due to the very early nature of this insult. The neurovascular unit, including vascular leptomeningeal cells (VLMCs), mural cells, endothelial cells, astrocytes, and microglia, showed strong upregulation of genes involved in TNF signaling, cellular responses to cytokine stimuli, and cytokine signaling in the immune system.

Conversely, downregulated genes were enriched in pathways related to the disruption of metabolic and structural functions, including genes involved in maintaining the blood-brain barrier (BBB). Cell-cell communication analysis also identified significant rewiring of intercellular signaling in the septic brain, with an overall increase in the number and strength of cell to cell interactions in the E. coli pigs compared to saline controls.

In saline controls, cell-cell communication was dominated by homeostatic signaling from microglia and astrocytes. In contrast, the septic pigs showed a significant shift toward inflammatory and immune-related signaling pathways, mainly involving microglia and astrocytes, along with the emergence of signaling pathways from mural cells and VLMCs. Our findings reveal that systemic sepsis triggers a rapid shift from homeostatic to inflammatory signaling within the neurovascular unit, driven by the emergence of pro-inflammatory crosstalk between vascular cells, astrocytes, and microglia.

This porcine model effectively captures the acute transcriptional landscape of the septic brain, offering a critical window for therapeutic strategies aimed at stabilizing the BBB and preventing long-term cognitive decline in sepsis survivors.