Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell Host Microbe. 2012 Sep 13;12(3):313-23. doi: 10.1016/j.chom.2012.07.012.
Nitric oxide (NO) defends against intracellular pathogens, but its synthesis must be regulated due to cell and tissue toxicity. During infection, macrophages import extracellular arginine to synthesize NO, generating the byproduct citrulline. Accumulated intracellular citrulline is thought to fuel arginine synthesis catalyzed by argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl), which would lead to abundant NO production. Instead, we find that citrulline is exported from macrophages during early stages of NO production with <2% retained for recycling via the Ass1-Asl pathway. Later, extracellular arginine is depleted, and Ass1 expression allows macrophages to synthesize arginine from imported citrulline to sustain NO output. Ass1-deficient macrophages fail to salvage citrulline in arginine-scarce conditions, leading to their inability to control mycobacteria infection. Thus, extracellular arginine fuels rapid NO production in activated macrophages, and citrulline recycling via Ass1 and Asl is a fail-safe system that sustains optimum NO production.
一氧化氮（NO）可抵御细胞内病原体，但因其具有细胞毒性和组织毒性，其合成必须受到调控。在感染期间，巨噬细胞会从细胞外摄取精氨酸以合成 NO，产生副产物瓜氨酸。人们认为，积累的细胞内瓜氨酸为精氨酸合成提供燃料，由精氨酸合成酶（Ass1）和精氨酸琥珀酸裂解酶（Asl）催化，从而导致大量 NO 产生。然而，我们发现，在 NO 产生的早期阶段，瓜氨酸从巨噬细胞中输出，只有<2%的瓜氨酸通过 Ass1-Asl 途径进行回收再利用。随后，细胞外的精氨酸被耗尽，Ass1 的表达使巨噬细胞能够从输入的瓜氨酸合成精氨酸，以维持 NO 的产生。在精氨酸匮乏的条件下，Ass1 缺陷型巨噬细胞无法回收瓜氨酸，导致其无法控制分枝杆菌感染。因此，细胞外的精氨酸为激活的巨噬细胞快速产生 NO 提供燃料，而通过 Ass1 和 Asl 进行瓜氨酸循环是维持最佳 NO 产生的备用系统。
