Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase
Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase
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DOI：
10.1002/eji.200425883
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发表时间：
2005-04-01
影响因子：
5.4
通讯作者：
Hajishengallis, G
中科院分区：
文献类型：
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作者：
Harokopakis, E;Hajishengallis, G
CD11b-CD18和其他整合素在免疫和炎症中发挥重要作用，需要事先通过内向外信号激活才能有效地结合其配体。我们提出了一种新的tlr2依赖信号通路的证据，该信号通路通过CD14识别牙龈卟啉单胞菌菌毛，导致人类单核细胞或中性粒细胞中CD11b-CD18的激活。CD11b- cd18的活化结合状态涉及诱导构象变化，通过检测CD11b的活化特异性表位来监测。针对TLR2的单抗显著抑制了菌毛诱导这一活化表位的能力，但对TLR4或不相关的表面分子则没有作用。此外，纤毛活化CD11b-CD18的能力被磷脂酰肌醇-3激酶的药理抑制剂显著抑制，而PKC或p38丝裂原活化蛋白激酶则不受抑制。由菌毛激活的信号通路不同于由n -甲酰基met - leu - phe激活的信号通路，n -甲酰基met - leu - phe是一种典型的整合素激活剂，因为前者对百日咳毒素不敏感。TLR2作为病原体诱导的CD11b-CD18激活的信号受体的这种新功能可能在感染驱动的慢性炎症条件中发挥重要作用，如牙周病或动脉粥样硬化，其中牙龈卟啉卟啉菌已被涉及。
CD11b-CD18 and other integrins play important roles in immunity and inflammation and require prior activation through inside-out signaling to efficiently bind their ligands. We present evidence for a novel TLR2-dependent signaling pathway that leads to CD11b-CD18 activation in human monocytes or neutrophils upon recognition of Porphyromonas gingivalis fimbriae through CD14. The activated binding-state of CD11b-CD18, which involves induction of conformational changes, was monitored through detection of an activation-specific epitope of CD11b. The ability of fimbriae to induce this activation epitope was significantly inhibited by a mAb to TLR2, but not to TLR4 or unrelated surface molecules. Moreover, the ability of fimbriae to activate CD11b-CD18 was significantly inhibited by pharmacological inhibitors of phosphatidylinositol-3-kinase but not of PKC or of p38 mitogen-activated protein kinase. The signaling pathway activated by fimbriae is distinct from that which is activated by N-formyl-Met-Leu-Phe, a prototypical integrin activator, since the former was insensitive to pertussis toxin. This novel function of TLR2 as a signaling receptor for pathogen-induced activation of CD11b-CD18 may play a significant role in infection-driven chronic inflammatory conditions, such as periodontal disease or atherosclerosis, where P. gingivalis has been implicated.