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^1,2,3,4. 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.

哺乳动物免疫系统使用各种模式识别受体来识别入侵者和宿主损伤，并将该信息传递给下游免疫代谢信号转导结果。含漆酶结构域 1 (LACC1) 蛋白是一种在炎症性巨噬细胞中高度表达的酶，在多种炎症性疾病（如炎症性肠病、关节炎和清除微生物感染 1,2,3,4）中起着重要的调节^作用。然而，LACC1 功能所需的生化作用在很大程度上仍未明确。在这里，我们阐明了 LACC1 在小鼠和人类中的共同生化功能，将l-瓜氨酸转化为l-鸟氨酸 ( l-Orn) 和异氰酸，并作为促炎性一氧化氮合酶 (NOS2) 和多胺免疫代谢之间的桥梁。我们在小鼠模型和鼠伤寒沙门氏菌感染的骨髓源性巨噬细胞中验证了 NOS2、LACC1 和鸟氨酸脱羧酶 1 (ODC1) 之间的遗传和机制联系。引人注目的是，LACC1 表型需要上游 NOS2 和下游 ODC1，并且Lacc1 ^-/-与其产物l -Orn 的化学互补显着恢复了野生型活性。我们的研究结果阐明了炎症性巨噬细胞中以前未发现的途径，解释了为什么它的缺陷可能导致人类炎症性疾病，并表明l-Orn 可以作为一种营养品来改善 LACC1 相关的免疫功能障碍，例如关节炎或炎症性肠病。