TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae
TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae
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DOI：
10.4049/jimmunol.176.12.7645
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Hajishengallis, George
中科院分区：
文献类型：
--
作者：
Harokopakis, Evlambia;Albzreh, Mohamad H.;Hajishengallis, George
我们目前的证据表明，一种新的TLR 2功能，在transmodulating粘附活动的人单核细胞在响应的菌毛牙龈卟啉单胞菌，病原体牵连在慢性牙周炎和动脉粥样硬化。单核细胞募集到内皮下是动脉粥样硬化的关键步骤，我们研究了牙龈卟啉单胞菌菌毛在刺激单核细胞粘附到内皮细胞和跨内皮迁移中的作用。菌毛诱导CD 11b/CD 18依赖性粘附的人单核细胞或小鼠巨噬细胞的内皮受体ICAM-1，这些活动被抑制TLR 2的封锁或缺陷或PI 3 K的药理学抑制剂。此外，这种可诱导的粘附活性对艰难梭菌毒素B的作用敏感，但不受肉毒梭菌C3外切酶、百日咳毒素或霍乱毒素的影响。因此，我们随后通过使用小GTP酶的显性负信号突变体表明，Rac 1介导菌毛刺激的单核细胞结合ICAM-1的能力。Rac 1的显性负突变体也抑制了PI 3 K的脂质激酶活性，表明Rac 1在该促粘附途径中作用于PI 3 K的上游。此外，菌毛刺激单核细胞粘附到HUVEC和跨HUVEC单层的迁移;这两种活动都需要TLR 2和Rac 1信号传导，并依赖于ICAM-1和高亲和力状态的CD 11b/CD 18。牙龈炎刺激的单核细胞显示增强的跨内皮迁移与nonfimbriated同基因突变体刺激的单核细胞相比。因此，牙龈卟啉单胞菌菌毛激活人单核细胞中的一种新的促粘附途径，涉及TLR 2、Rac 1、PI 3 K和CD 11b/CD 18，这可能构成牙龈卟啉单胞菌与炎性动脉粥样硬化过程联系的机制基础。
We present evidence for a novel TLR2 function in transmodulating the adhesive activities of human monocytes in response to the fimbriae of Porphyromonas gingivalis, a pathogen implicated in chronic periodontitis and atherosclerosis. Monocyte recruitment into the subendothelium is a crucial step in atherosclerosis, and we investigated the role of P. gingivalis fimbriae in stimulating monocyte adhesion to endothelial cells and transendothelial migration. Fimbriae induced CD11b/CD18-dependent adhesion of human monocytes or mouse macrophages to endothelial receptor ICAM-1; these activities were inhibited by TLR2 blockade or deficiency or by pharmacological inhibitors of PI3K. Moreover, this inducible adhesive activity was sensitive to the action of Clostridium difficile toxin B, but was not affected by Clostridium botulinum C3 exoenzyme, pertussis toxin, or cholera toxin. Accordingly, we subsequently showed through the use of dominant negative signaling mutants of small GTPases, that Rac1 mediates the ability of fimbria-stimulated monocytes to bind ICAM-1. A dominant negative mutant of Rac1 also inhibited the lipid kinase activity of PI3K suggesting that Rac1 acts upstream of PI3K in this proadhesive pathway. Furthermore, fimbriae stimulated monocyte adhesion to HUVEC and transmigration across HUVEC monolayers; both activities required TLR2 and Rac1 signaling and were dependent upon ICAM-1 and the high-affinity state of CD11b/CD18. A gingivalis-stimulated monocytes displayed enhanced transendothelial migration compared with monocytes stimulated with nonfimbriated isogenic mutants. Thus, P. gingivalis fimbriae activate a novel proadhesive pathway in human monocytes, involving TLR2, Rac1, PI3K, and CD11b/CD18, which may constitute a mechanistic basis linking P. gingivalis to inflammatory atherosclerotic processes.