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

ABSTRACT: 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, TNFα, 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE283884 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:BACKGROUND: SLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear.METHODS: We collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS and CD14 changes.RESULTS: Elevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response.CONCLUSION: Our study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE.

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

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