Abstract

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.