In monocytes, the fimbriae of the oral pathogen Porphyromonas gingivalis activate cross talk signaling from Toll-like receptor 2 (TLR2) to the beta2 integrin CD11b/CD18, leading to the induction of the high-affinity state of the latter receptor. CD14 plays an important role in this "inside-out" proadhesive pathway by binding fimbriae and facilitating the activation of TLR2 and phosphatidylinositol 3-kinase signaling. In its high-affinity state, CD11b/CD18 mediates monocyte adhesion to endothelial cells and transmigration to sites of infection. We have now shown that P. gingivalis fimbriae function as both an activator and a ligand of CD11b/CD18; thus, fimbriae proactively promote their own binding to monocytes. Indeed, treatments that interfered with fimbria-induced activation of CD11b/CD18 (i.e., blockade of CD14, TLR2, or phosphatidylinositol 3-kinase signaling) also suppressed the cell binding activity of fimbriae, which was largely inducible and CD11b/CD18 dependent. Development of a recombinant inside-out signaling system in Chinese hamster ovary cells confirmed the ability of fimbriae to activate CD14/TLR2 signaling and induce their own CD11b/CD18-dependent binding. Induction of this proadhesive pathway by P. gingivalis fimbriae appeared to take place in lipid rafts. Indeed, methyl-beta-cyclodextrin, a cholesterol-sequestering agent that disrupts lipid raft organization, was found to inhibit the fimbria-induced assembly of CD14/TLR2 signaling complexes and the activation of the high-affinity state of CD11b/CD18. Experiments using macrophages from mice deficient in various pattern recognition receptors indicated that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating P. gingivalis internalization within macrophages. It therefore appears that P. gingivalis proactively modulates beta2 integrin adhesive activity for intracellular uptake.

译文

在单核细胞中,口腔病原体牙龈卟啉单胞菌的菌毛激活从Toll样受体2 (TLR2) 到 β2整合素CD11b/CD18的串扰信号,导致诱导后者受体的高亲和力状态。CD14通过结合菌毛并促进TLR2和磷脂酰肌醇3-激酶信号的激活,在这种 “由内而外” 的前粘附途径中起重要作用。在其高亲和力状态下,CD11b/CD18介导单核细胞与内皮细胞的粘附并转移到感染部位。我们现在已经证明,牙龈卟啉单胞菌菌毛既是CD11b/CD18的激活剂又是配体。因此,菌毛会主动促进其自身与单核细胞的结合。实际上,干扰菌毛诱导的CD11b/CD18激活 (即CD14,TLR2或磷脂酰肌醇3-激酶信号传导的阻断) 的治疗也抑制了菌毛的细胞结合活性,这在很大程度上是可诱导的并且CD11b/CD18依赖性。在中国仓鼠卵巢细胞中开发了重组的由内而外信号系统,证实了菌毛激活CD14/TLR2信号并诱导其自身CD11b/CD18-dependent结合的能力。牙龈卟啉单胞菌诱导这种前粘附途径似乎发生在脂质筏中。实际上,发现甲基-β-环糊精是一种破坏脂质筏组织的胆固醇螯合剂,可抑制菌毛诱导的CD14/TLR2信号复合物的组装以及CD11b/cd18高亲和力状态的激活。使用缺乏各种模式识别受体的小鼠的巨噬细胞进行的实验表明,参与由内而外的前粘附途径 (CD14,TLR2和CD11b/CD18) 的受体对于介导巨噬细胞内牙龈卟啉单胞菌内化很重要。因此,似乎牙龈卟啉单胞菌主动调节 β2整合素粘附活性以促进细胞内摄取。

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