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

d-amino acids have been detected in various tissues; however, whether d-amino acids shape immune cell (e.g., macrophages) function remains undefined. Here, we demonstrated that inflammatory macrophages decrease mRNA expression of d-amino acid oxidase (DAAO) and d-aspartate oxidase (DDO) through nuclear factor κB (NF-κB) signaling. Notably, inhibition of DAAO or DDO increases the concentration of intracellular d-amino acids, consequently suppressing IL-1β release. Mechanistically, d-amino acids inhibit the formation of gasdermin D (GSDMD) oligomer via GSDMD-K146 acetylation. d-amino acids directly bind and increase the enzyme activity of mitochondrial pyruvate dehydrogenase (PDH), resulting in acetyl-coenzyme A production for acetylation. Consistently, d-Ala/d-Glu supplementation or myeloid-specific deletion of DDO attenuates lipopolysaccharides (LPS)-induced sepsis in mice. Collectively, our study reveals a mechanism involving acetylation mediated by d-amino acids in regulation of macrophage function, providing a potential therapeutic strategy for treating macrophage-associated inflammatory diseases.