A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase.
Bottom Line: 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.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.
Affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01309 Dresden, Germany Institute of Physiology, Technische Universität Dresden, 01309 Dresden, Germany email@example.com.Show MeSH
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Mentions: Rapid integrin activation is required for integrin-dependent leukocyte adhesion. In an effort to assess whether ligation of TLRs could induce rapid integrin-dependent adhesion, we studied the effect of coincubation with TLR1-9 ligands on leukocyte adhesion to immobilized ligands, using a 20-min adhesion assay. The β2-integrin–dependent adhesion (Smith et al., 1989) of THP-1 myelomonocytic cells to immobilized ICAM-1 was assessed. In addition, THP-1 cell adhesion to fibronectin was studied, which is mediated by both β1- and β2-integrins (Owen et al., 1992; Frieser et al., 1996). As a control, adhesion to immobilized BSA was assessed. Whereas several TLR ligands seemingly stimulated slightly the adhesion of THP-1 cells to ICAM-1 and fibronectin but not to bovine serum albumin (BSA), a significant increase of cell adhesion to ICAM-1 or fibronectin was consistently observed with HKLM, flagellin, and FSL-1, which stimulate TLR2, TLR5, and TLR2/6, respectively (Figure 1, A and B). Moreover, ligation of the same TLRs (TLR2, TLR5, and TLR2/6) induced adhesion of primary human neutrophils to immobilized ICAM-1 (Figure 1C). Therefore in the subsequent studies we used TLR2 and TLR5 ligands to assess the effects of TLR-dependent activation of leukocyte adhesion, whereas the TLR9 ligand ODN2006, which had the weakest effect in stimulating integrin-dependent leukocyte adhesion, was used as a negative control. Together these data unequivocally suggested that acute (within 20 min) TLR2 and TLR5 ligation is capable of inducing rapid integrin-dependent leukocyte adhesion, a property that is traditionally attributed to activation of leukocytes by chemokines or selectin ligands.
Affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01309 Dresden, Germany Institute of Physiology, Technische Universität Dresden, 01309 Dresden, Germany firstname.lastname@example.org.