The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation.
The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation.
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DOI：
10.1084/jem.20131706
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发表时间：
2014-08-25
期刊：
影响因子：
--
通讯作者：
Filippi MD
中科院分区：
文献类型：
--
作者：
Kumar S;Xu J;Kumar RS;Lakshmikanthan S;Kapur R;Kofron M;Chrzanowska-Wodnicka M;Filippi MD
缺乏小GTd-Rap 1b的小鼠表现出增强的中性粒细胞向炎症肺的募集，并通过增强PI 3 K-Akt活化对内毒素休克易感。中性粒细胞是细胞防御感染和炎性损伤的第一道防线。然而，中性粒细胞活化和积聚到组织中由于释放过多的有毒氧化剂和蛋白酶而触发组织损伤，这是急性肺损伤（ALI）的原因。尽管其临床意义，中性粒细胞迁移的分子调控知之甚少。小的GTdR Rap 1b通常被认为是通过控制双向整合素信号传导的免疫细胞功能的正调节剂。然而，我们发现Rap 1b缺陷小鼠表现出增强的中性粒细胞募集到发炎的肺部，并增强了对内毒素休克的易感性。出乎意料的是，Rap 1b缺陷促进了通过内皮细胞的跨细胞渗出途径。体外Rap 1b缺陷中性粒细胞跨细胞迁移的增加通过增强的PI 3 K-Akt激活和侵袭足样突起选择性介导。Akt抑制在体内抑制过度Rap 1b缺陷的中性粒细胞迁移和相关的内毒素休克。Rap 1b对PI 3 K信号的抑制作用可能是通过激活磷酸酶SHP-1介导的。因此，这项研究揭示了Rap 1b作为中性粒细胞迁移和肺部炎症的关键抑制因子的意想不到的作用。
Mice lacking the small GTPase Rap1b exhibit enhanced neutrophil recruitment to inflamed lungs and susceptibility to endotoxin shock via enhance PI3K-Akt activation. Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.
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DOI：
10.1007/978-1-61779-166-6_18
发表时间：
2011-01-01
期刊：
INTEGRIN AND CELL ADHESION MOLECULES: METHODS AND PROTOCOLS
影响因子：
--
作者：
Katagiri, Koko;Kinashi, Tatsuo
通讯作者：
Kinashi, Tatsuo
影响因子：
4.4
作者：
Carman, CV;Jun, CD;Springer, TA
通讯作者：
Springer, TA
影响因子：
20.3
作者：
Kumar, Sachin;Xu, Juying;Filippi, Marie-Dominique
通讯作者：
Filippi, Marie-Dominique
影响因子：
30.5
作者：
Katagiri, K;Maeda, A;Kinashi, T
通讯作者：
Kinashi, T
DOI：
10.1084/jem.20100040
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Awasthi A;Samarakoon A;Chu H;Kamalakannan R;Quilliam LA;Chrzanowska-Wodnicka M;White GC 2nd;Malarkannan S
通讯作者：
Malarkannan S