Cocr Microparticles Induce A Robust Type 2 Innate Immune Response That is Dependent on Syk and Btk Signaling

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. Intra-peritoneal inoculation of CoCr induces a robust innate type 2 response with increases in M2 macrophages, eosinophils, and neutrophils and this response is dependent on Spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK) signaling, but not TLR, Caspase-1, or Cyclooxygenase signaling. We have also shown that this robust response is independent of T and B cell signaling. To examine this response in a more clinically relevant murine model, bilateral intra-articular knee injections of CoCr microparticles were given to C57BL/6 mice and changes in different innate immune cells were assessed from knee synovial cell isolates. Administration of the SYK inhibitor BAY 61-3606, or the BTK inhibitor Ibrutinib, abrogated innate immune cell recruitment and M2 macrophage polarization which is otherwise observed 2 days after inoculation with CoCr microparticles. The presence of M2 macrophages (CD68+, CD206+, and CD163+) is also observed in human peri-prosthetic tissue samples obtained from patients undergoing revision joint arthroplasty. Taken together, our findings suggest that BTK signaling is required for the type 2 inflammatory response to CoCr microparticles, providing a potential novel target for control of harmful inflammation leading to fibrosis and aseptic loosening.