A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase.
A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase.
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DOI：
10.1091/mbc.e14-04-0867
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发表时间：
2014-10-01
影响因子：
3.3
通讯作者：
Chavakis T
中科院分区：
文献类型：
--
作者：
Chung KJ;Mitroulis I;Wiessner JR;Zheng YY;Siegert G;Sperandio M;Chavakis T
TLR 2和TLR 5连接直接诱导β2-整联蛋白活化，促进细胞与ICAM-1的粘附。全身性体内施用TLR 2配体Pam 3CSK 4在数分钟内增加了与内皮的整合素依赖性粘附。连接TLR连接与β2-整合素活化的信号通路涉及Rac-1、NADPH氧化酶2和Rap 1-GT3。快速β2-整联蛋白活化对于白细胞粘附和募集到感染部位是必不可少的，并且由趋化因子或P-选择素糖蛋白配体-1诱导的由内而外信号传导介导。在这里，我们发现了一种新的途径，快速激活整合素依赖性白细胞粘附，触发toll样受体（TLR）介导的信号。TLR 2或TLR 5连接迅速激活整合素依赖性白细胞粘附到固定的ICAM-1和纤连蛋白。一致的是，在提睾肌模型中通过活体显微镜鉴定，体内给予TLR 2配体Pam 3CSK 4在几分钟内增加了整合素依赖性慢滚动和与内皮的粘附。TLR 2和TLR 5连接增加β2-整联蛋白亲和力，如通过检测活化依赖性新表位所评估。TLR 2和TLR 5触发的白细胞整合素激活需要增强Rap 1 GT3活性，这是由Rac 1激活和NADPH氧化酶-2依赖性活性氧产生介导的。这种新的直接途径将TLR对病原体的初始识别与β2-整合素的快速激活联系起来，可能对急性白细胞浸润至病原体侵袭部位起关键性调节作用。
TLR2 and TLR5 ligation directly induces β2-integrin activation, promoting cell adhesion to ICAM-1. Systemic in vivo administration of the TLR2 ligand Pam3CSK4 increases integrin-dependent adhesion to endothelium within minutes. The signaling pathway linking TLR ligation with β2-integin activation involves Rac-1, NADPH oxidase 2, and Rap1-GTPase. Rapid β2-integrin activation is indispensable for leukocyte adhesion and recruitment to sites of infection and is mediated by chemokine- or P-selectin glycoprotein ligand-1–induced inside-out signaling. Here we uncovered a novel pathway for rapid activation of integrin-dependent leukocyte adhesion, triggered by toll-like receptor (TLR)–mediated signaling. TLR2 or TLR5 ligation rapidly activated integrin-dependent leukocyte adhesion to immobilized ICAM-1 and fibronectin. Consistently, in vivo administration of the TLR2-ligand Pam3CSK4 increased integrin-dependent slow rolling and adhesion to endothelium within minutes, as identified by intravital microscopy in the cremaster model. TLR2 and TLR5 ligation increased β2-integrin affinity, as assessed by the detection of activation-dependent neoepitopes. TLR2- and TLR5-triggered integrin activation in leukocytes required enhanced Rap1 GTPase activity, which was mediated by Rac1 activation and NADPH oxidase-2–dependent reactive oxygen species production. This novel direct pathway linking initial pathogen recognition by TLRs to rapid β2-integrin activation may critically regulate acute leukocyte infiltration to sites of pathogen invasion.