Molecular Mechanisms Involved in Interleukin-1β Release by Macrophages Exposed to Metal Ions from Implantable Biomaterials

Metal ions released from implantable biomaterials have been associated with adverse biological reactions that can limit implant longevity. Previous studies have shown that, in macrophages, Co2+, Cr3+, and Ni2+ can activate the NLR family pyrin domain-containing protein 3 (NLPR3) inflammasome, which is responsible for interleukin(IL)-1β production through caspase-1. Furthermore, these ions are known to induce oxidative stress, and inflammasome priming is known to involve nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. However, the mechanisms of inflammasome activation by metal ions remain largely unknown. The objectives of this thesis were to determine if, in macrophages: 1. IL-1β release induced by metal ions is caspase-1-dependent; 2. caspase-1 activation and IL-1β release induced by metal ions are oxidative stress-dependent; and 3. IL-1β release induced by metal ions is NF-κB signaling pathway-dependent. Lipopolysaccharide (LPS)-primed murine bone-marrow-derived macrophages were exposed to Co2+, Cr3+, or Ni2+, with or without an inhibitor of caspase-1, oxidative stress, or NF-κB. Culture supernatants were analyzed for active caspase-1 (immunoblotting) and/or IL-1β (ELISA). Overall, results showed that while both Cr3+ and Ni2+ may be inducing inflammasome activation, Cr3+ is likely a more potent activator, acting through oxidative stress and the NF-κB signaling pathway. Further elucidation of the activation mechanisms may facilitate the development of therapeutic approaches to modulate the inflammatory response to metal ions, and thereby increase implant longevity.

Grantor dc:publisher

Université d'Ottawa / University of Ottawa

Year dc:date

2018

Author dc:creator

• Ferko, Maxime-Alexandre

Contributors dc:contributor

• Catelas, Isabelle

• bioengineering
• biomedical engineering
• biomaterials
• biocompatibility
• orthopaedics
• implants
• metal alloys
• metal ions
• adverse tissue reactions
• immune response
• inflammation
• molecular mechanisms
• inflammasome activation
• NLRP3
• NALP3
• macrophages
• bone marrow-derived macrophages

Language dc:language

en

Identifier

http://dx.doi.org/10.20381/ruor-21603

OAI identifier oai:identifier

oai:ruor.uottawa.ca:10393/37331