Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase.
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.
Harokopakis
Evlambia
E
Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70119, USA.
Hajishengallis
George
G
D039481:CD11b Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D010861:Fimbriae, Bacterial / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D039481:CD11b Antigen; D018821:CD18 Antigens; D016023:Integrins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases