title: A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase.
abstract: Rapid β2-integrin activation is indispensable for leukocyte adhesion and recruitment to sites of infection and is mediated by chemokine- or P-selectin glycoprotein ligand-1-induced inside-out signaling. Here we uncovered a novel pathway for rapid activation of integrin-dependent leukocyte adhesion, triggered by toll-like receptor (TLR)-mediated signaling. TLR2 or TLR5 ligation rapidly activated integrin-dependent leukocyte adhesion to immobilized ICAM-1 and fibronectin. Consistently, in vivo administration of the TLR2-ligand Pam3CSK4 increased integrin-dependent slow rolling and adhesion to endothelium within minutes, as identified by intravital microscopy in the cremaster model. TLR2 and TLR5 ligation increased β2-integrin affinity, as assessed by the detection of activation-dependent neoepitopes. TLR2- and TLR5-triggered integrin activation in leukocytes required enhanced Rap1 GTPase activity, which was mediated by Rac1 activation and NADPH oxidase-2-dependent reactive oxygen species production. This novel direct pathway linking initial pathogen recognition by TLRs to rapid β2-integrin activation may critically regulate acute leukocyte infiltration to sites of pathogen invasion.
authors: Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01309 Dresden, Germany Institute of Physiology, Technische Universität Dresden, 01309 Dresden, Germany kyoung-jin.chung@uniklinikum-dresden.de.
authors: Kyoung-Jin
authors: KJ
authors: Chung
authors: Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01309 Dresden, Germany Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01309 Dresden, Germany.
authors: Ioannis
authors: I
authors: Mitroulis
authors: Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians Universität, 80539 Munich, Germany.
authors: Johannes R
authors: JR
authors: Wiessner
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
authors: Ying Yi
authors: YY
authors: Zheng
authors: Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01309 Dresden, Germany.
authors: Gabriele
authors: G
authors: Siegert
authors: Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians Universität, 80539 Munich, Germany.
authors: Markus
authors: M
authors: Sperandio
authors: Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01309 Dresden, Germany Institute of Physiology, Technische Universität Dresden, 01309 Dresden, Germany Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01309 Dresden, Germany Department of Medicine III, Technische Universität Dresden, 01309 Dresden, Germany.
authors: Triantafyllos
authors: T
authors: Chavakis
mesh_terms: D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004727:Endothelium / Q000378:metabolism; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051198:Toll-Like Receptor 5 / Q000819:agonists*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D018821:CD18 Antigens; D005353:Fibronectins; D055666:Lipopeptides; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; C508075:Pam(3)CSK(4) peptide; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; C495342:TLR2 protein, human; C495346:TLR5 protein, human; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D018799:Intercellular Adhesion Molecule-1; D009247:NADH, NADPH Oxidoreductases; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D020827:rap1 GTP-Binding Proteins