<jats:title>ABSTRACT</jats:title><jats:p>In monocytes, the fimbriae of the oral pathogen<jats:italic>Porphyromonas gingivalis</jats:italic>activate cross talk signaling from Toll-like receptor 2 (TLR2) to the β<jats:sub>2</jats:sub>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<jats:italic>P. gingivalis</jats:italic>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<jats:italic>P. gingivalis</jats:italic>fimbriae appeared to take place in lipid rafts. Indeed, methyl-β-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<jats:italic>P. gingivalis</jats:italic>internalization within macrophages. It therefore appears that<jats:italic>P. gingivalis</jats:italic>proactively modulates β<jats:sub>2</jats:sub>integrin adhesive activity for intracellular uptake.</jats:p>