Impaired macrophage function underscores susceptibility to Salmonella in mice lacking Irgm1 (LRG-47)
Impaired macrophage function underscores susceptibility to Salmonella in mice lacking Irgm1 (LRG-47)
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DOI：
10.4049/jimmunol.179.10.6963
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Taylor, Gregory A.
中科院分区：
文献类型：
--
作者：
Henry, Stanley C.;Daniell, Xiaojou;Taylor, Gregory A.
IRG蛋白或免疫相关GTP酶（也称为p47 GTP酶）是一组在感染后高度表达的IFN调节蛋白。这些蛋白定位于细胞内膜，包括感染的巨噬细胞和其他宿主细胞中含有病原体的空泡。目前的数据表明，IRG蛋白Irgm 1（LRG-47）对于细胞内细菌的抗性至关重要。这种功能被认为是调节宿主细胞中空泡细菌存活的结果。在目前的工作中，Irgm 1在控制鼠伤寒沙门氏菌耐药性的作用进行了探索，以进一步确定该蛋白调节宿主耐药性的机制。irgm 1缺陷小鼠表现出对这种细菌的易感性增加，这反映在脾脏和肝脏中细菌负荷增加以及S.鼠伤寒肉芽肿这些小鼠还表现出无法将巨噬细胞聚集在细菌沉积部位。在体外，Irgm 1缺陷型巨噬细胞抑制S.鼠伤寒沙门氏菌受损。此外，与IFN-γ激活后，Irgm 1缺陷的巨噬细胞的粘附性和运动性显着下降。这些细胞的粘附/运动性改变伴随着细胞形态、粘附相关蛋白密度和肌动蛋白染色的变化。总之，这些数据表明，除了调节含病原体的空泡的成熟，Irgm 1在调节活化的巨噬细胞的粘附和运动性中起着关键作用。
IRG proteins, or immunity-related GTPases (also known as p47 GTPases), are a group of IFN-regulated proteins that are highly expressed in response to infection. The proteins localize to intracellular membranes including vacuoles that contain pathogens in infected macrophages and other host cells. Current data indicate that the IRG protein Irgm1 (LRG-47) is critical for resistance to intracellular bacteria. This function is thought to be a consequence of regulating the survival of vacuolar bacteria in host cells. In the current work, the role of Irgm1 in controlling resistance to Salmonella typhimurium was explored to further define the mechanism through which the protein regulates host resistance. Irgm1-deficient mice displayed increased susceptibility to this bacterium that was reflected in increased bacterial loads in spleen and liver and decreased maturation of S. typhimurium granulomas. The mice also displayed an inability to concentrate macrophages at sites of bacterial deposition. In vitro, the ability of Irgm1-deficient macrophages to suppress intracellular growth of S. typhimurium was impaired. Furthermore, adhesion and motility of Irgm1-deficient macrophages after activation with IFN-gamma was markedly decreased. Altered adhesion/motility of those cells was accompanied by changes in cell morphology, density of adhesion-associated proteins, and actin staining. Together, these data suggest that in addition to regulating the maturation of pathogen-containing vacuoles, Irgm1 plays a key role in regulating the adhesion and motility of activated macrophages.