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Scientific article
English

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

Contributors

Shang, Limin; Daubeuf, Bruno; Triantafilou, Martha; Olden, Robin; Depis, Fabien; Raby, Anne-Catherine; Herren, Suzanne; Dos Santos, Anaelle; Malinge, Pauline; Dunn-Siegrist, Irène; Benmkaddem, Sanae; Geinoz, Antoine; Magistrelli, Giovanni; Rousseau, François Jean Robert; Buatois, Vanessa; Salgado-Pires, Susana; Reith, Walter; Monteiro, Renato; Pugin, Jérôme; Leger, Olivier Max; Ferlin, Walter; Kosco-Vilbois, Marie; Triantafilou, Kathy; Elson, Greg

Published in

The Journal of biological chemistry, vol. 289, no. 22, p. 15309-15318

Publication date

2014

Abstract

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.

Keywords

  • 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

UNIGE affiliation entities

UNIGE research groups

Citation (ISO format)

SHANG, Limin et al. Selective antibody intervention of Toll-like receptor 4 activation through Fc γ receptor tethering. In: The Journal of biological chemistry, 2014, vol. 289, n° 22, p. 15309–15318. doi: 10.1074/jbc.M113.537936

Main files (1)

Article (Published version)

Identifiers

Journal ISSN

0021-9258
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Technical informations

Creation

14/10/2014 15:17:00

First validation

14/10/2014 15:17:00

Update

14/03/2023 22:20:24

Status update

14/03/2023 22:20:23

Last indexation

30/10/2024 21:01:26
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