Research Papers: Immunology:

Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation

Helen Lawrence, Amy Elizabeth Mawdesley, James Patrick Holland, John Andrew Kirby, David John Deehan and Alison Jane Tyson-Capper _

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Oncotarget. 2016; 7:7578-7585. https://doi.org/10.18632/oncotarget.7105

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Helen Lawrence1,*, Amy Elizabeth Mawdesley1,*, James Patrick Holland2, John Andrew Kirby1, David John Deehan1,2 and Alison Jane Tyson-Capper1

1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

2 Musculoskeletal Services, Freeman Hospital, Newcastle upon Tyne, UK

* Joint first authors

Correspondence to:

Alison Tyson-Capper, email:

Keywords: cobalt, metal-on-metal, antibody, TLR4, inflammation, Immunology and Microbiology Section, Immune response, Immunity

Received: December 16, 2015 Accepted: January 23, 2016 Published: January 31, 2016


Cobalt-chrome alloy is a widely used biomaterial in joint replacements, dental implants and spinal rods. Although it is an effective and biocompatible material, adverse reactions to metal debris (ARMD) have arisen in a minority of patients, particularly in those with metal-on-metal bearing hip replacements. There is currently no treatment for ARMD and once progressive, early revision surgery of the implant is necessary. Therapeutic agents to prevent, halt or reverse ARMD would therefore be advantageous.

Cobalt ions activate Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to bacterial lipopolysaccharide (LPS) resulting in the production of pro-inflammatory cytokines and chemokines. We hypothesised that anti-TLR4 neutralising antibodies, reported to inhibit TLR4-mediated inflammation, could prevent the inflammatory response to cobalt ions in an in vitro macrophagecell culture model.

This study shows that a monoclonal anti-TLR4 antibody inhibited cobalt-mediated increases in pro-inflammatory IL8, CCL20 and IL1A expression, as well as IL-8 secretion. In contrast, a polyclonal antibody did not prevent the effect of cobalt ions on either IL-8 or IL1A expression, although it did have a small effect on the CCL20 response. Interestingly, both antibodies inhibited cobalt-mediated neutrophil migration although the greater effect was observed with the monoclonal antibody.

In summary our data shows that a monoclonal anti-TLR4 antibody can inhibit cobalt-mediated inflammatory responses while a polyclonal antibody only inhibits the effect of specific cytokines. Anti-TLR4 antibodies have therapeutic potential in ARMD although careful antibody design is required to ensure that the LPS response is preserved.

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