The role of Vitamin B12 and TCN2 in modulating inflammatory responses in sepsis

Sepsis remains a significant challenge in critical care, with early inflammation and infection control being key therapeutic hurdles. Recent studies have highlighted the potential role of vitamin B12 in modulating immune responses and its therapeutic applications in sepsis. This study investigates the impact of vitamin B12 and its transport protein, transcobalamin II (TCN2), on macrophage polarization and inflammatory responses in sepsis. We found that vitamin B12 levels are significantly reduced in sepsis patients and correlate negatively with pro-inflammatory cytokines such as IL-6, TNFa, and CRP. In mouse models, vitamin B12 supplementation improved survival rates, reduced lung injury, and modulated macrophage polarization towards an anti-inflammatory M2 phenotype. Mechanistically, vitamin B12 interacts with PTGS2, promoting its degradation and inhibiting PGE2 production. TCN2, the key transporter of vitamin B12, regulates TLR4 activation and macrophage M1 polarization. TCN2 knockout mice exhibited reduced inflammation and improved survival in LPS-induced sepsis, but increased bacterial load in CLP models. Additionally, TCN2 enhances glucose uptake and glycolysis through interaction with GLUT1, promoting M1 macrophage polarization. These findings suggest that vitamin B12 and TCN2 play crucial roles in modulating the inflammatory response and could be potential therapeutic targets in sepsis. Overall design: RNA-seq profilling of wildtype and TCN2 cKO of BMDMs from mice.