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.