Sterile type 2 inflammation triggered by microparticles is abrogated by inhibition of IL33 through blockade of Bruton’s tyrosine kinase

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 IL4, IL5, IL13, IL33, M2 macrophages, eosinophils and neutrophils compared to controls given vehicle only. Blockade of the SYK signaling pathway with the inhibitor BAY 61-3606 or the down stream BTK signaling pathway with Ibrutinib abrogated the CoCr-mediated innate type 2 inflammation. Further studies in CBA/Nxid mice, a genetic BTK loss of function mutant also showed decreases in type 2 inflammation, confirming a critical role for BTK in CoCr mediated sterile type 2 inflammation. Inoculation of JH−/−, B cell deficient mice, or depletion of T cells by anti-CD4 (GK1.5) antibody, had no impact on CoCr mediated type 2 inflammation. We further demonstrated that the major source of IL33 was macrophages and intra-peritoneal administration of recombinant IL33 rescued the CoCr mediated type 2 response after BTK blockade. These studies indicate that the type 2 immune response caused by solid particles is abrogated by blockade of BTK signaling pathways and that exogenous IL33 is sufficient to rescue this response. These studies elucidate the nature of wear debris-mediated type 2 sterile inflammation and provide potential targets for future therapy.