An interesting review concerning the role of D-AAs, and their metabolism, in the innate immune system has been recently reported by (Sasabe and Suzuki, 2018).

D-amino acid oxidase (DAAO), the enzyme deputed to D-AAs degradation, is present in granule fraction of human neutrophilic leukocytes (Eckstein et al., 1971): by oxidizing D-AAs, DAAO generates hydrogen peroxide. It has been proposed that hydrogen peroxide, chloride ions and myeloperoxidase form a potent bactericidal system. DAAO has been also proposed to be located on the membrane of neutrophilic leukocytes: following phagocytosis, DAAO produces hydrogen peroxide within phagosomes (Robinson et al., 1978), although this conclusion is still debated. Actually, a model was proposed by (Sasabe and Suzuki, 2018) in which aromatic D-AAs (such as D-Phe and D-Tyr) chemo-attract human neutrophils (probably thorough GPR109B, a G protein-coupled receptor) (Irukayama-Tomobe et al., 2009) and these cells eliminate bacteria through D-AAs oxidation within phagosome. Bacteria can survive to DAAO activity through actively importing D-AAs (e.g., D-Ala is imported by dalS, an ABC importer in S. typhimorium).

DAAO is also present in the luminal epithelium of the small intestine of animals (and humans): notably, its level is induced by feeding carps with D-Ala (Sarower et al., 2003). In Muc2-positive secretory vesicles of goblet cells and of enterocytes (Sasabe et al., 2016) DAAO expression is induced by vancomycin-sensitive intestinal microbes and it is released to modulate the gut microbiota. This effect can be due to hydrogen peroxide generation by DAAO-catalyzed oxidation of bacterial D-AAs, which limits colonization of pathogenic bacteria (such as Vibrio cholerae, a good producer of D-Met) and favours commensal bacteria Lactobacilli (which are resistant to hydrogen peroxide).

D-AAs, such as D-Leu and D-Phe found in respiratory isolates of Staphylococcus species, can inhibit the innate immune response by preventing the release of antimicrobial peptides through sweet taste receptors (i.e. T1R2/3) and in this way can modulate the microbial community of the upper airways (Lee et al., 2017). Notably, D-Trp in mice ameliorates allergic airway inflammation and hyper-responsiveness (Kepert et al., 2017).