Inflammation

Exposure to wear and corrosion products is associated not only with the activation of macrophages but also with the activation of osteoblasts and other stromal cells involved in the process of material-induced inflammation. In order to identify the various cellular mechanisms that lead to osteolysis, it is necessary to investigate the initial contact of the cells with the wear products. To achieve this, it must be clarified whether the binding of the wear products to receptors on the cell surface is sufficient to induce intracellular signaling cascades and inflammasome-associated processes or whether these are only initiated by active uptake of the wear products into the cell. Thereby, specific physicochemical properties of the materials for the differential recognition and uptake mechanisms have to be considered. These processes are accompanied by the intracellular activation of various signaling cascades that lead to the release of signaling molecules, which not only activate other cells in the peri-implant tissue but also trigger a systemic reaction. In addition, the intracellular uptake of the wear and corrosion products can lead to irreversible material-dependent cell damage.

Metal wear and corrosion products from implanted biomaterials modulate the immune response. They directly or indirectly interact with immune cell receptors and induce the release of inflammatory cytokines as well as cell death. We propose that the NLRP3 inflammasome, an intracellular molecular sensor, has a central role in these processes. Activation of the NLRP3 inflammasome leads to the release of mature IL-1β via a form of cell death known as pyroptosis that is mediated by gasdermin (Gsdm) D.
Staphylococcus aureus bacteria are a major cause of prosthetic joint infection necessitating revision arthroplasty, a huge burden on patient health. Numerous bacterial compounds can activate the NLRP3 inflammasome and induce IL-1β release. This suggests that metal wear and corrosion products and S. aureus synergize in the induction of inflammation and host cell death. Finally, metals ions (Co²⁺, Ni²⁺), as well as certain S. aureus virulence factors (proteases and enterotoxins) induce “allergic” type 2 inflammation. What are the common mechanisms?
This project aims to clarify the interrelations between metal wear and corrosion products and S. aureus with inflammasome activation, cell death and allergy.

Besides the inflammatory reaction, certain metal compounds can influence cellular processes in various ways. For example, different divalent metal ions (e.g., Co²⁺) activate the hypoxia-induced factor 1α, which in turn affects the energy metabolism and differentiation status of exposed cells and tissue (increased glycolysis, stem cell activation, induction of vascularization). In addition, corrosion products can cause oxidative stress. Overall, exposure to metallic wear and corrosion products can trigger biochemical reactions that may promote the chronification of the inflammatory process. These reactions are difficult to control in individual cases and significantly impact the degree of differentiation or the immunological response. Further, it is still unclear to what extent released wear and corrosion products affect cells of the implant periphery in their antimicrobial activity against typical implant-infecting bacteria. In that context, it will also be studied whether metallic degradation products influence the biofilm formation of the bacteria and can thus increase susceptibility to infection.