title: Porphyromonas gingivalis fimbriae proactively modulate beta2 integrin adhesive activity and promote binding to and internalization by macrophages.
abstract: 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.
authors.affiliation: University of Louisville Health Sciences Center, 501 South Preston Street, Room 206, Louisville, KY 40292, USA. g0haji01@louisville.edu
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Evlambia
authors.initials: E
authors.lastname: Harokopakis
authors.forename: Martha
authors.initials: M
authors.lastname: Triantafilou
authors.forename: Kathy
authors.initials: K
authors.lastname: Triantafilou
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion / Q000276:immunology*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D010861:Fimbriae, Bacterial / Q000502:physiology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000276:immunology; D010587:Phagocytosis; D016966:Porphyromonas gingivalis / Q000472:pathogenicity*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D016056:Immunodominant Epitopes; D018950:Lipopolysaccharide Receptors; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2