LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages

The mammalian immune system employs various pattern recognition receptors (PRRs) to recognize invaders and host damage and transmits this information to downstream immunometabolic signaling outcomes. Laccase domain-containing 1 (LACC1) protein is an enzyme highly expressed in inflammatory macrophages and serves a central regulatory role in multiple inflammatory diseases, such as in inflammatory bowel diseases (IBDs), arthritis, and clearance of microbial infection(1-4). However, the biochemical roles required for LACC1 functions remain largely undefined. Here, we elucidated a shared biochemical function of LACC1 in mice and humans, converting L-citrulline (L-Cit) to L-ornithine (L-Orn) and isocyanic acid (HNCO) and serving as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism. We validated the genetic and mechanistic connections among NOS2, LACC1, and ornithine decarboxylase 1 (ODC1) in mouse models and bone marrow derived macrophages (BMDMs) infected by Salmonella enterica Typhimurium. Strikingly, LACC1 phenotypes required upstream NOS2 and downstream ODC1, and Lacc1(−/−) chemical complementation with its product L-Orn could significantly restore wildtype activities. Our findings illuminate a previously unidentified pathway in inflammatory macrophages, explain why its deficiency may contribute to human inflammatory diseases, and suggest that L-Orn could serve as a nutraceutical to ameliorate LACC1-associated immunological dysfunctions such as arthritis or IBD.