Brain endothelial cells undergo metabolic reprogramming in response to systemic inflammation in experimental sepsis.

Sepsis causes a systemic shift from a proinflammatory acute response to an immunosuppressive late immune response after seven days. In the brain, sepsis causes microvascular dysfunction, blood-brain barrier (BBB) breakdown, and subsequent cognitive impairment. While numerous studies have shown that metabolic changes reprogram peripheral tissue immune responses in sepsis, whether these changes also occur in the brain remains unclear. We hypothesized that systemic inflammation in sepsis induces metabolic reprogramming in brain microvascular endothelial cells (BMECs), one of the primary cellular components of the BBB. Our study used the Seahorse XF Analyzer to assess the role of metabolic reprogramming in BMECs and cortical micro-punches. Results showed that isolated BMECs from sepsis-primed 2-3 month old male mice who received a cecal ligation and puncture (CLP) showed increased ATP production, maximal respiration, and glycolytic reserve. In contrast, cortical tissue micro-punches from CLP mice, which contain all brain cells, showed diminished ATP production. To assess parallel peripheral immune responses in late sepsis, we observed a significant reduction in CD8+ splenocytes and an upregulation of myeloid drive suppressor cells (MDSCs) highlighting the immunosuppressive nature of late sepsis. These results demonstrate that metabolic reprogramming of BMECs may protect the brain from peripheral immune dysfunction during late sepsis.