d-amino acids restrain macrophage IL-1β release through gasdermin D acetylation.

Summary

This study uncovers that d-amino acids suppress macrophage IL-1β release by inducing GSDMD K146 acetylation, thereby blocking pore-forming oligomerization. d-Amino acids activate mitochondrial PDH to boost acetyl-CoA, and either d-Ala/d-Glu supplementation or myeloid DDO deletion ameliorates LPS-induced sepsis in mice.

Key Findings

• Inflammatory macrophages downregulate DAAO/DDO via NF-κB; inhibition increases intracellular d-amino acids and suppresses IL-1β release.
• d-Amino acids induce GSDMD K146 acetylation, preventing GSDMD oligomerization and pore formation.
• d-Amino acids directly enhance mitochondrial PDH activity to increase acetyl-CoA for acetylation.
• d-Ala/d-Glu supplementation or myeloid-specific DDO deletion attenuates LPS-induced sepsis in mice.

Clinical Implications

Highlights a druggable immunometabolic node—enhancing GSDMD acetylation to restrain IL-1β release—suggesting adjunctive strategies (e.g., targeted d-amino acid therapy or DDO/DAAO modulation) to mitigate macrophage-driven inflammation in sepsis.

Limitations

• Primary reliance on LPS-induced sepsis; generalizability to polymicrobial sepsis remains to be tested.
• Human translational data (dose, safety, pharmacokinetics of d-amino acids) are not provided.

Future Directions

Validate in polymicrobial sepsis (e.g., CLP), assess human macrophage ex vivo responses, and develop pharmacologic strategies to modulate GSDMD acetylation safely in early-phase trials.