Selective antibody intervention of Toll-like receptor 4 activation through Fc γ receptor tethering

Article Article scientifique Article Selective antibody intervention of Toll-like receptor 4 activation through Fc γ receptor tethering eng 2014 author Shang Limin author Daubeuf Bruno author Triantafilou Martha author Olden Robin author Depis Fabien 665380 author Raby Anne-Catherine author Herren Suzanne author Dos Santos Anaelle author Malinge Pauline author Dunn-Siegrist Irène 119480 author Benmkaddem Sanae author Geinoz Antoine 607378 author Magistrelli Giovanni author Rousseau François Jean Robert 89516 author Buatois Vanessa author Salgado-Pires Susana author Reith Walter 25482 author Monteiro Renato author Pugin Jérôme 69624 author Leger Olivier Max 500370 author Ferlin Walter author Kosco-Vilbois Marie author Triantafilou Kathy author Elson Greg 15309-15318 10.1074/jbc.M113.537936 24737331 0021-9258 Inflammation is mediated mainly by leukocytes that express both Toll-like receptor 4 (TLR4) and Fc γ receptors (FcγR). Dysregulated activation of leukocytes via exogenous and endogenous ligands of TLR4 results in a large number of inflammatory disorders that underlie a variety of human diseases. Thus, differentially blocking inflammatory cells while sparing structural cells, which are FcγR-negative, represents an elegant strategy when targeting the underlying causes of human diseases. Here, we report a novel tethering mechanism of the Fv and Fc portions of anti-TLR4 blocking antibodies that achieves increased potency on inflammatory cells. In the presence of ligand (e.g. lipopolysaccharide (LPS)), TLR4 traffics into glycolipoprotein microdomains, forming concentrated protein platforms that include FcγRs. This clustering produces a microenvironment allowing anti-TLR4 antibodies to co-engage TLR4 and FcγRs, increasing their avidity and thus substantially increasing their inhibitory potency. Tethering of antibodies to both TLR4 and FcγRs proves valuable in ameliorating inflammation in vivo. This novel mechanism of action therefore has the potential to enable selective intervention of relevant cell types in TLR4-driven diseases. Animals Antibodies, Monoclonal/immunology Binding Sites CHO Cells Cell Line Cricetulus Dimerization Female Humans Inflammation/immunology/metabolism Macrophages/cytology/immunology Membrane Microdomains/immunology/metabolism Mice Mice, Inbred C57BL Receptors, IgG/immunology/metabolism Toll-Like Receptor 4/chemistry/immunology/metabolism U937 Cells Dewey 616.07 137 Département de pathologie et immunologie 21F false 321 Groupe Pugin Jérôme (Soins intensifs) 587 221 Groupe Reith Walter (pathologie et immunologie) 282 The Journal of biological chemistry 289 22 3fa624bf-b26c-474e-87ec-51e23199ab50 Article (Published version) Restricted J. Biol. Chem.-2014-Shang-15309-18.pdf 2489878 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Rousseau, François Jean Robert