CoCr micro-particles induce a robust type 2 inflammation in knee synovial tissues leading to fibrosis and tissue damage

Abstract

Abstract Cobalt chrome (CoCr) is a major component of orthopaedic implants and a source of metallic wear debris, which may contribute to harmful inflammation and implant failure. In this study we show that the presence of M2 macrophages (CD68+, CD206+, and CD163+) and tissue fibrosis is observed in human peri-prosthetic tissue samples obtained from patients undergoing revision joint arthroplasty. We further examined the molecular mechanisms that drive the sterile inflammatory response to CoCr microparticles in 2 clinically relevant murine articular models. Bilateral intra-articular knee injections of CoCr microparticles were given to C57BL/6 mice and innate immune cell infiltrates were examined in both acute (2 day) and chronic (2 week) models. At the acute time point, CoCr microparticles induce inflammation characterized by an innate type 2 response in synovial tissues with marked increases in neutrophils, eosinophils, and M2 macrophages. This response in articular tissues is dependent on both SYK and BTK signaling as pharmacologic blockade of either pathway abrogates the innate response. Studies in our chronic model demonstrates that repeated exposure of articular tissues to CoCr microparticles triggers an inflammatory response that is characterized by persistent innate cell infiltrates of neutrophils and macrophages, as well as the development of tissue fibrosis. Additionally we show that the innate response and generation of tissue fibrosis in our chronic model is independent of the Caspase-1 inflammasome. Taken together, our findings suggest that CoCr mediates a robust type 2 inflammation that leads to fibrosis and identifies novel potential targets for control of microparticle induced sterile inflammatory responses.