Metal sensitivity can de defined as an inflammatory response caused by excessive immune reactivity to metals. While various sources of metal exposure can induce metal sensitivity reactions in humans, metal orthopedic implants are particularly of concern because they generate large quantities of soluble and particulate debris for extended periods of time in vivo. Metal implant debris can be found localized around the implant tissue or distributed systemically in secondary lymphoid organs and non-lymphoid tissues. In light of these observations, we hypothesized that monocytes/macrophages uptake soluble and particulate metal debris generated from orthopedic implants and trigger a proinflammatory response that can lead to metal-specific CD4⁺ T cell activation in certain "metal allergic" individuals.

Here we determine that both soluble (metal ions) and particulate (> 0.1 uM particles) implant metals induce differential proinflammatory responses in human macrophages that is partly mediated by the NALP3 inflammasome "danger signaling" pathway. We found that monocytes/macrophages exposed to implant metals secrete potent proinflammatory cytokines like IL-1β (NALP-3-, ASC-, and caspase 1-dependent) IL-6, TNFα and can differentially upregulate T cell co-stimulatory molecules CD80, CD86 and ICAM-1. We also found that proliferation and activation induced surface markers CD69 and CD25 are upregulated in autologous CD4⁺ T cells after exposure to soluble and particulate metals in an in vitro co-culture model, where depletion of T regulatory cells exacerbated the response to metals.

Potentially, the ability to pre-determine innate and adaptive immune responses to implant metals in vitro prior to exposure to metal components in vivo could serve as an essential diagnostic function in a clinical setting for individuals receiving metal prosthesis.