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

Zebiao Wu1, Qilin Hu1, Yinhao Shen1

  • 1State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Laboratory of Lingnan Modern Agriculture, College of Animal Science, South China Agricultural University, Guangzhou 510642, China.

Science Advances
|April 29, 2026
PubMed

Insights

d-amino acids regulate macrophage function by suppressing inflammatory cytokine release through acetylation. This finding offers a potential therapeutic strategy for inflammatory diseases.

Area of Science:

  • Immunology
  • Biochemistry
  • Cell Biology

Background:

  • D-amino acids are present in tissues, but their role in immune cell function is unclear.
  • Macrophages are key immune cells involved in inflammatory responses.

Purpose of the Study:

  • To investigate the role of d-amino acids in regulating macrophage function.
  • To elucidate the molecular mechanisms by which d-amino acids influence inflammation.

Main Methods:

  • Studied the expression of d-amino acid oxidase (DAAO) and d-aspartate oxidase (DDO) in macrophages.
  • Investigated the effect of DAAO/DDO inhibition on intracellular d-amino acid levels and IL-1β release.
  • Examined the mechanism of gasdermin D (GSDMD) oligomerization and its regulation by d-amino acids.
  • Assessed the impact of d-amino acid supplementation and DDO deletion on LPS-induced sepsis in mice.

Main Results:

  • Inflammatory macrophages downregulate DAAO and DDO via NF-κB signaling.
  • Inhibiting DAAO or DDO increases intracellular d-amino acids, suppressing IL-1β release.
  • D-amino acids inhibit GSDMD oligomerization through acetylation, mediated by increased acetyl-CoA from pyruvate dehydrogenase (PDH) activity.
  • D-Ala/d-Glu supplementation or DDO deletion attenuated LPS-induced sepsis in mice.

Conclusions:

  • D-amino acids regulate macrophage inflammatory function through acetylation-dependent inhibition of GSDMD.
  • This mechanism involves the PDH-acetyl-CoA pathway and impacts IL-1β release.
  • Targeting d-amino acid metabolism presents a potential therapeutic strategy for inflammatory diseases.

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