Cobalt-chrome micro-particles induce a robust MyD88-independent type 2 immune response (IRM7P.495)

Abstract

Abstract Orthopaedic wear debris may contribute to harmful inflammation and implant failure. In this study, we examined whether Cobalt Chrome (CoCr) can trigger inflammatory responses under aseptic conditions. Intra-peritoneal injection of mice with CoCr microparticles induced a type 2 innate immune response with marked increases in M2 macrophages, neutrophils and eosinophils in WT and MYD88/TRIF-/- mice. In contrast, although Th2 cytokine MRNA elevations were intact, a marked decrease in neutrophil and M2 macrophages occurred in Caspase-1-/- mice compared to wild type mice. SYK pathway blockade with the inhibitor BAY 61-3606 caused a marked general decrease in type 2 inflammation. Adjuvant properties of CoCr particles were assessed by immunizing mice with CoCr+OVA peptide after transfer of CFSE-labeled OVA specific DO11.10 CD4+ T cells. After 7 days, marked increases in OVA-specific T cell proliferation and IL-4 production were observed compared to mice immunized with OVA alone. To more closely approximate effects of wear debris in joint replacements, localized immune cell infiltrates were examined after intra-articular knee injections of CoCr particles. Infiltration of specific immune cells and mRNA expression were similar to peritoneal inoculation. These studies indicate that the type 2 immune response is triggered by solid particles, independent of toll like receptor signalling, and differentially modulated by Inflammasome and SYK signaling pathways