Metal ions activate vascular endothelial cells and increase lymphocyte chemotaxis and binding

Ninomiya, James T.; Kuzma, Scott A.; Schnettler, Timothy J.; Krolikowski, John G.; Struve, Janine; Weihrauch, Dorothée

doi:10.1002/jor.22377

Cited by 26 publications

(28 citation statements)

References 41 publications

(46 reference statements)

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“…Even the concentrations at the lower end of the range are considerably higher than those detected in the serum and synovial fluid of patients with failed MoM implants [17-19]. However, the Co 2+ concentrations used in our study are in line with those of similar in vitro studies of the inflammatory effects of metal ions [3, 10, 20, 21]. Hence, they are appropriate and relevant for this study.…”

Section: Discussionsupporting

confidence: 69%

“…This was inhibited by the TLR4 antagonist CLI-095, showing that the receptor is central to the responses. Previous studies have shown that Co 2+ upregulates adhesion molecule expression [8-10], but have not demonstrated the exact signalling pathways involved. The data obtained in this study supports the findings of these studies and also indicates a previously unidentified role for TLR4 in Co 2+ -mediated ICAM1 expression in both endothelial cells and macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Effect of cobalt-mediated Toll-like receptor 4 activation on inflammatory responses in endothelial cells

et al. 2016

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Cobalt-containing metal-on-metal hip replacements are associated with adverse reactions to metal debris (ARMD), including inflammatory pseudotumours, osteolysis, and aseptic implant loosening. The exact cellular and molecular mechanisms leading to these responses are unknown. Cobaltions (Co2+) activate human Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to Gram negative bacterial lipopolysaccharide (LPS).We investigated the effect of Co2+-mediated TLR4 activation on human microvascular endothelial cells (HMEC-1), focusing on the secretion of key inflammatory cytokines and expression of adhesion molecules. We also studied the role of TLR4 in Co2+-mediated adhesion molecule expression in MonoMac 6 macrophages.We show that Co2+ increases secretion of inflammatory cytokines, including IL-6 and IL-8, in HMEC-1. The effects are TLR4-dependent as they can be prevented with a small molecule TLR4 antagonist. Increased TLR4-dependent expression of intercellular adhesion molecule 1 (ICAM1) was also observed in endothelial cells and macrophages. Furthermore, we demonstrate for the first time that Co2+ activation of TLR4 upregulates secretion of a soluble adhesion molecule, sICAM-1, in both endothelial cells and macrophages. Although sICAM-1 can be generated through activity of matrix metalloproteinase-9 (MMP-9), we did not find any changes in MMP9 expression following Co2+ stimulation.In summary we show that Co2+ can induce endothelial inflammation via activation of TLR4. We also identify a role for TLR4 in Co2+-mediated changes in adhesion molecule expression. Finally, sICAM-1 is a novel target for further investigation in ARMD studies.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Effect of cobalt-mediated Toll-like receptor 4 activation on inflammatory responses in endothelial cells

et al. 2016

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“…Heavy metal ions including Zn 2+ , Ni 2+ , Co 2+ , and Cr 3+ were also shown to increase the activity of immune cells, e.g. polymorphonuclear neutrophil granulocytes (PMNs) [99], macrophages [100], and lymphocytes [101]. Interestingly, low concentrations of Zn 2+ ions activated the secretion of pro-inflammatory mediators from PMNs and increased PMN-EC binding [99].…”

Section: Discussionmentioning

confidence: 99%

Cytocompatibility and early inflammatory response of human endothelial cells in direct culture with Mg-Zn-Sr alloys

et al. 2017

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Crystalline Mg-Zinc (Zn)-Strontium (Sr) ternary alloys consist of elements naturally present in the human body and provide attractive mechanical and biodegradable properties for a variety of biomedical applications. The first objective of this study was to investigate the degradation and cytocompatibility of four Mg-4Zn-xSr alloys (x = 0.15, 0.5, 1.0, 1.5 wt%; designated as ZSr41A, B, C, and D respectively) in the direct culture with human umbilical vein endothelial cells (HUVEC) in vitro. The second objective was to investigate, for the first time, the early-stage inflammatory response in cultured HUVECs as indicated by the induction of vascular cellular adhesion molecule-1 (VCAM-1). The results showed that the 24-h in vitro degradation of the ZSr41 alloys containing a β-phase with a Zn/Sr at% ratio ~1.5 was significantly faster than the ZSr41 alloys with Zn/Sr at% ~1. Additionally, the adhesion density of HUVECs in the direct culture but not in direct contact with the ZSr41 alloys for up to 24 h was not adversely affected by the degradation of the alloys. Importantly, neither culture media supplemented with up to 27.6 mM Mg2+ ions nor media intentionally adjusted up to alkaline pH 9 induced any detectable adverse effects on HUVEC responses. In contrast, the significantly higher, yet non-cytotoxic, Zn2+ ion concentration from the degradation of ZSr41D alloy was likely the cause for the initially higher VCAM-1 expression on cultured HUVECs. Lastly, analysis of the HUVEC-ZSr41 interface showed near-complete absence of cell adhesion directly on the sample surface, most likely caused by either a high local alkalinity, change in surface topography, and/or surface composition. The direct culture method used in this study was proposed as a valuable tool for studying the design aspects of Zn-containing Mg-based biomaterials in vitro, in order to engineer solutions to address current shortcomings of Mg alloys for vascular device applications.

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“…83–85 Metal ions also suppress osteoblast function and activate endothelium to recruit mononuclear cells. 86–88 Following the seminal discovery that nickel ions activate TLR4 signaling, it was recently demonstrated that cobalt ions can also induce TLR4 signaling by binding to and cross-linking the receptor protein, thus providing a direct mechanism by which also cobalt ions could activate macrophages and other cells directly. 28–30 …”

Section: Metal Wear and The Role Of Adaptive Immune Systemmentioning

confidence: 99%

Innate Immune Reactions in Septic and Aseptic Osteolysis around Hip Implants

Pajarinen

Jämsen

Konttinen

et al. 2014

J Long Term Eff Med Implants

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According to the long-standing definition, septic and aseptic total joint replacement loosening are two distinct conditions with little in common. Septic joint replacement loosening is driven by bacterial infection whereas aseptic loosening is caused by biomaterial wear debris released from the bearing surfaces. However, recently it has been recognized that the mechanisms that drive macrophage activation in septic and aseptic total joint replacement loosening resemble each other. In particular, accumulating evidence indicates that in addition to mediating bacterial recognition and the subsequent inflammatory reaction, toll-like receptors (TLRs) and their ligands, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS), play a key role in wear debris-induced inflammation and macrophage activation. In addition, subclinical bacterial biofilms have been identified from some cases of seemingly aseptic implant loosening. Furthermore, metal ions released from some total joint replacements can activate TLR signaling similar to bacterial derived PAMPs. Likewise, metal ions can function as haptens activating the adaptive immune system similar to bacterial derived antigens. Thus, it appears that aseptic and septic joint replacement loosening share similar underlying pathomechanisms and that this strict dichotomy to sterile aseptic and bacterial-caused septic implant loosening is somewhat questionable. Indeed, rather than being two, well-defined clinical entities, peri-implant osteolysis is, in fact, a spectrum of conditions in which the specific clinical picture is determined by complex interactions of multiple local and systemic factors.

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Metal ions activate vascular endothelial cells and increase lymphocyte chemotaxis and binding

Cited by 26 publications

References 41 publications

Effect of cobalt-mediated Toll-like receptor 4 activation on inflammatory responses in endothelial cells

Effect of cobalt-mediated Toll-like receptor 4 activation on inflammatory responses in endothelial cells

Cytocompatibility and early inflammatory response of human endothelial cells in direct culture with Mg-Zn-Sr alloys

Innate Immune Reactions in Septic and Aseptic Osteolysis around Hip Implants

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