Desaminotyrosine is a redox‐active microbial metabolite that bolsters macrophage antimicrobial functions while attenuating IL‐6 production

Abstract Intestinal microbiota contributes to host defense against pathogens while avoiding the induction of inflammation in homeostatic conditions, but the mechanism is not fully understood. To investigate the potential role of the bacterial metabolite desaminotyrosine (DAT) in regulating host defense and inflammation, we pretreated mouse bone marrow‐derived macrophages (BMDMs) with DAT for 12 hours and then challenged with bacterial lipopolysaccharide (LPS). We found that DAT priming‐enhanced type I interferon response while selectively inhibiting proinflammatory interleukin (IL)‐6 production after exposure to LPS. This is related to the fact that DAT is a natural antioxidant determined by radical scavenging assay in a cell‐free system. DAT‐primed cells had increased levels of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) upon LPS stimulation. Countering the increased NADPH by supplementing extra oxidized NADP + to cells reversed DAT's effect on LPS‐induced Il‐6 and interferon‐stimulated gene expressions. DAT‐primed cells also were more resistant to oxidative stress‐induced generation of reactive oxygen species and cell death. DAT promoted the production of antimicrobial effector nitric oxide in a cellular redox‐dependent manner, leading to enhanced macrophage antimicrobial activity during Salmonella enterica infection. Our data suggest that DAT acts as a host‐microbiota crosstalk signal in shaping host immune defense and inflammatory response.