Yan Chunguang, Wang Ximo, Liu Yanlan, Abdulnour Raja-Elie, Wu Min, Gao Hongwei
Department of Anesthesiology, Perioperative&Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
Department of Surgery, Tianjin Nankai Hospital, Tianjin, China.
PLoS One. 2015 Oct 15;10(10):e0140804. doi: 10.1371/journal.pone.0140804. eCollection 2015.
Growing evidences indicate that Ly-GDI, an inhibitory protein of Rho GTPases, plays an essential role in regulating actin cytoskeletal alteration which is indispensible for the process such as phagocytosis. However, the role of Ly-GDI in inflammation remains largely unknown. In the current study, we found that Ly-GDI expression was significantly decreased in the IgG immune complex-injured lungs. To determine if Ly-GDI might regulate the lung inflammatory response, we constructed adenovirus vectors that could mediate ectopic expression of Ly-GDI (Adeno-Ly-GDI). In vivo mouse lung expression of Ly-GDI resulted in a significant attenuation of IgG immune complex-induced lung injury, which was due to the decreased pulmonary permeability and lung inflammatory cells, especially neutrophil accumulation. Upon IgG immune complex deposition, mice with Ly-GDI over-expression in the lungs produced significant less inflammatory mediators (TNF-α, IL-6, MCP-1, and MIP-1α) in bronchoalveolar lavage fluid when compared control mice receiving airway injection of Adeno-GFP. Mechanically, IgG immune complex-induced NF-κB activity was markedly suppressed by Ly-GDI in both alveolar macrophages and lungs as measured by luciferase assay and electrophoretic mobility shift assay. These findings suggest that Ly-GDI is a critical regulator of inflammatory injury after deposition of IgG immune complexes and that it negatively regulates the lung NF-κB activity.
越来越多的证据表明，Rho GTPases的抑制蛋白Ly-GDI在调节肌动蛋白细胞骨架改变中起重要作用，而这种改变对于吞噬作用等过程是不可或缺的。然而，Ly-GDI在炎症中的作用仍 largely未知。在当前研究中，我们发现Ly-GDI在IgG免疫复合物损伤的肺组织中表达显著降低。为了确定Ly-GDI是否可能调节肺部炎症反应，我们构建了能够介导Ly-GDI异位表达的腺病毒载体（腺病毒-Ly-GDI）。在体内小鼠肺组织中表达Ly-GDI导致IgG免疫复合物诱导的肺损伤显著减轻，这是由于肺通透性降低和肺部炎症细胞，尤其是中性粒细胞积聚减少。在IgG免疫复合物沉积后，与接受气道注射腺病毒绿色荧光蛋白（Adeno-GFP）的对照小鼠相比，肺组织中Ly-GDI过表达的小鼠支气管肺泡灌洗液中产生的炎症介质（肿瘤坏死因子-α、白细胞介素-6、单核细胞趋化蛋白-1和巨噬细胞炎性蛋白-1α）明显减少。从机制上讲，通过荧光素酶测定和电泳迁移率变动分析测量，Ly-GDI在肺泡巨噬细胞和肺组织中均显著抑制IgG免疫复合物诱导的核因子-κB活性。这些发现表明，Ly-GDI是IgG免疫复合物沉积后炎症损伤的关键调节因子，并且它对肺组织中的核因子-κB活性起负调节作用。
