Cobalt ions recruit inflammatory cells in vitro through human Toll-like receptor 4

Abstract

Metal-on-metal (MoM) hip replacements, often manufactured from a cobalt-chrome alloy, are associated with adverse reactions including soft tissue necrosis and osteolysis. Histopathological analysis of MoM peri-implant tissues reveals an inflammatory cell infiltrate that includes macrophages, monocytes and neutrophils.Toll-like receptor 4 (TLR4) is an innate immune receptor activated by bacterial lipopolysaccharide. Recent studies have demonstrated that cobalt ions from metal-on-metal joints also activate human TLR4, increasing cellular secretion of inflammatory chemokines including interleukin-8 (IL-8, CXCL8) and CCL2. Chemokines recruit immune cells to the site of inflammation, and their overall effect depends on the chemokine profile produced.This study investigated the effect of cobalt on the secretion of inflammatory cytokines CCL20 and IL-6. The chemotactic potential of conditioned media from a cobalt-stimulated human monocyte cell line on primary monocytes and neutrophils was investigated using an in vitro transwell migration assay. The role of TLR4 in observed effects was studied using a small molecule TLR4-specific antagonist.Cobalt ions significantly increased release of CCL2 and IL-6 by MonoMac 6 cells (P<0.001). Conditioned media from cobalt-stimulated cells significantly increased monocyte and neutrophil chemotaxis in vitro (P<0.001). These effects were abrogated by the TLR4 antagonist (P<0.001) suggesting that they occur through cobalt activation of TLR4.This study demonstrates the role of TLR4 in cobalt-mediated immune cell chemotaxis and provides a potential mechanism by which cobalt ions may contribute to the immune cell infiltrate surrounding failed metal hip replacements. It also highlights the TLR4 signalling pathway as a potential therapeutic target in preventing cobalt-mediated inflammation.

Studies of molecular pathways associated with blood neutrophil corticosteroid insensitivity in equine asthma

“…Although in vitro detection of many inflammatory mediators was not significantly altered by either hypoxia or LPS stimulation in neutrophils (231), others have shown an increase in IL-8 gene and protein expression in CoCl 2 -induced hypoxia conditions in human endothelial cells (232). In contrast to our results, it has been reported that CoCl 2 increases the release of inflammatory cytokines through TLR4 pathways in immune cells like monocytes and neutrophils (233,234).…”

Analysis of Cellular Activity and Induction of Inflammation in Response to Short-Term Exposure to Cobalt and Chromium Ions in Mature Human Osteoblasts

“…This is also supported by TLR4 and IL6/IL8 results of Cr(3+) and Ni(2+) exposed cells. Lawrence and co-workers already showed, that Co(2+) activates TLR 4 which is in turn associated with enhanced chemokine release [39,40]. In contrast, Samelko et al (2016) reported that CoCr particles did not preferentially activate TLR4 induced inflammation [41].…”

Cobalt in athletes: hypoxia and doping - new crossroads

“…The ability of cobalt to induce apoptotic signaling was also demonstrated (Akbar et al, 2011). In line with induction of oxidative stress, cobalt was also capable of stimulation of proinflammatory milieu through proinflammatory cytokine overproduction, migration of immunocompetent cells via activation of Toll-like receptors 4 (TLR4) (Lawrence et al, 2016). Although cobalt-induced activation of HIF-1, being redox-and metal-sensitive transcription factor is considered as the key mechanism of physiological effect of cobalt, this process may also mediate certain toxic effects of cobalt exposure (Maxwell and Salnikow, 2004).…”