Tumor Necrosis Factor Primes and Metal Particles Activate the NLRP3 Inflammasome in Human Primary Macrophages

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Jämsen , E , Pajarinen , J , Kouri , V-P , Rahikkala , A , Goodman , S B , Manninen , M , Nordström , D C , Eklund , K K & Nurmi , K 2020 , ' Tumor Necrosis Factor Primes and Metal Particles Activate the NLRP3 Inflammasome in Human Primary Macrophages ' , Acta Biomaterialia , vol. 108 , pp. 347-357 . https://doi.org/10.1016/j.actbio.2020.03.017

Title: Tumor Necrosis Factor Primes and Metal Particles Activate the NLRP3 Inflammasome in Human Primary Macrophages
Author: Jämsen, Eemeli; Pajarinen, Jukka; Kouri, Vesa-Petteri; Rahikkala, Antti; Goodman, Stuart B.; Manninen, Mikko; Nordström, Dan C.; Eklund, Kari K.; Nurmi, Katariina
Contributor organization: HUS Internal Medicine and Rehabilitation
TRIMM - Translational Immunology Research Program
Department of Medicine
Division of Pharmaceutical Chemistry and Technology
Nanomedicines and Biomedical Engineering
HUS Inflammation Center
Date: 2020-05
Language: eng
Number of pages: 11
Belongs to series: Acta Biomaterialia
ISSN: 1742-7061
DOI: https://doi.org/10.1016/j.actbio.2020.03.017
URI: http://hdl.handle.net/10138/328098
Abstract: Aseptic loosening of total joint replacements is driven by a macrophage-mediated inflammatory reaction to implant-derived wear particles. Phagocytosis of implant debris has been suggested to activate the NLRP3 inflammasome leading to secretion of interleukin (IL)-1β. However, factors and molecular mechanisms driving the particle-induced inflammasome activation are yet to be fully elucidated. In this study, we investigated the inflammasome response of human primary macrophages to titanium, chromium, and molybdenum particles in vitro. We observed that particles alone were not sufficient to induce IL-1β secretion, but an additional priming signal—such as bacterial lipopolysaccharide (LPS)—was required to license the inflammasome activation. By using specific inhibitors against the inflammasome signaling pathway, we demonstrate that the particle-induced IL-1β secretion depended upon activation of the NLRP3 inflammasome. We further hypothesized that tumor necrosis factor (TNF) could substitute for LPS as a priming signal, and found that particle stimulation together with preceding TNF treatment resulted in inflammasome-dependent IL-1β production as well. Our results show that the NLRP3 inflammasome mediates wear particle responses in human primary macrophages, and its activation does not necessarily require the presence of bacterial components, but can be induced under aseptic conditions by TNF priming. Statement of Significance This study was conducted to elucidate the molecular mechanisms of metal particle-induced IL-1β secretion in human primary macrophages. Production of this pro-inflammatory mediator from wear particle-activated macrophages has been associated with increased bone loss around total joint replacements—a condition eventually requiring revision surgery. Our results confirm that together with a co-stimulatory priming signal, particles of common implant metals elicit macrophage-mediated IL-1β secretion through activation of the NLRP3 inflammasome pathway. We also present a concept of TNF priming in this context, demonstrating that the particle-related IL-1β secretion can take place in a truly sterile environment. Thus, inhibition of inflammasome signaling appears a means to prevent wear particle-induced inflammation and development of peri-prosthetic osteolysis.
IL-1 beta
Wear particle
216 Materials engineering
217 Medical engineering
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion

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