Blimp-1 orchestrates macrophage polarization and metabolic homeostasis via purine biosynthesis in sepsis.

Summary

Using in vivo CLP sepsis and in vitro macrophage models, the authors show Blimp-1 promotes M2 polarization by regulating purine biosynthesis and the Ornithine cycle. Blimp-1 knockdown worsened survival and tissue injury, positioning immune-metabolic control of macrophages as a potential therapeutic axis in sepsis.

Key Findings

• Blimp-1 expression is elevated in M2 macrophages during CLP-induced sepsis.
• Macrophage-targeted Blimp-1 knockdown reduces survival, increases tissue damage, and impairs M2 polarization in vivo.
• Blimp-1 promotes M2 polarization in BMDM, RAW264.7, and THP-1 cells by regulating purine biosynthesis and the Ornithine cycle.
• Metabolomics and dual-luciferase assays implicate purine biosynthesis as a key downstream pathway mediating Blimp-1 effects.

Clinical Implications

Although preclinical, targeting Blimp-1 or downstream purine biosynthesis pathways could modulate macrophage responses to mitigate organ injury in sepsis; translation will require human validation and safety studies.

Limitations

• Preclinical study without validation in human patient samples.
• Potential off-target or systemic effects of AAV-mediated knockdown were not fully dissected; rescue experiments were not reported.

Future Directions

Validate BLIMP1–purine biosynthesis axis in human sepsis samples, assess druggability (e.g., small-molecule modulators), and test efficacy/safety in large-animal models prior to early-phase clinical trials.