LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages

Article

关键词: NITRIC-OXIDE;    ORNITHINE-DECARBOXYLASE;    BOWEL-DISEASE;    ACTIVATION;    MICE;    MECHANISMS;    EXPRESSION;    GENERATION;    ITACONATE;    SYNTHASE;   

DOI  :  10.1038/s41586-022-05111-3

来源: SCIE

【 摘 要 】

The mammalian immune system uses various pattern recognition receptors to recognize invaders and host damage and transmits this information to downstream immunometabolic signalling 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 inflammatory bowel diseases, 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 to l-ornithine (l-Orn) and isocyanic acid 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 infected by Salmonella enterica Typhimurium. Strikingly, LACC1 phenotypes required upstream NOS2 and downstream ODC1, and Lacc1(-/-) chemical complementation with its product l-Orn significantly restored wild-type 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 inflammatory bowel disease.

【 授权许可】

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