Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll‐like receptor 2, and phosphatidylinositol‐3‐kinase

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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Porphyromonas gingivalis</jats:italic> 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 <jats:italic>N</jats:italic>‐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 <jats:italic>P. gingivalis</jats:italic> has been implicated.</jats:p>

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