Blockade of either SYK or BTK signaling pathways inhibits microparticle-induced type 2 inflammatory response (IRM11P.628)

Abstract

Abstract Wear debris microparticle release associated with total joint arthroplasty may contribute to harmful inflammation, osteolysis and implant failure. We examined the role of different molecular signaling pathways in microparticle-mediated inflammation. Intraperitoneal inoculation of cobalt chrome (CoCr) in mice induced a robust innate type 2 response with increases in Th2 cytokines, M2 macrophages, eosinophils and neutrophils compared to controls given vehicle only. Furthermore, this type 2 innate particle-induced response was independent of MYD88/TRIF and partially dependent on Caspase-1 signaling pathways. Blockade of the PGE-2 signaling pathway by administration of Aspirin or Celecoxib prior to CoCr inoculation caused a significant reduction in both neutrophils and macrophages with no effect on eosinophils and Th2 cytokines compared to the mice treated with CoCr + vehicle. Blockade of the SYK signaling pathway with the inhibitor BAY61-3606 or the BTK signaling pathway with Ibrutinib completely abrogated the CoCr-mediated innate inflammation and Th2 cytokines. These studies indicate that the type 2 immune response caused by solid particles is partially modulated by Caspase-1 and PGE-2 pathways and largely abrogated by blockade of upstream SYK and BTK signaling pathways. These studies provide potential targets for controlling the wear debris-mediated inflammation in synovial tissues that can contribute to aseptic loosening and implant failure.