Initiation of the innate sterile inflammatory response that can develop in response to microparticle (MP) exposure is little understood. A potent type 2 immune response associated with accumulation of neutrophils, eosinophils, and alternatively activated (M2) macrophages was observed in response to sterile MPs similar in size to wear debris associated with prosthetic implants. Although elevations in IL-33 and type 2 cytokines occurred independently of Caspase-1 inflammasome signaling, the response was dependent on Bruton’s tyrosine kinase (BTK). IL-33 was produced by macrophages and BTK-dependent expression of IL-33 by macrophages was sufficient to initiate the type 2 response. Analysis of inflammation in patient periprosthetic tissue also revealed type 2 responses under aseptic conditions in patients undergoing revision surgery. These findings indicate for the that MP-induced sterile inflammation is initiated by macrophages activated to produce IL-33. They further suggest that both BTK and IL-33 may provide therapeutic targets for wear debris induced periprosthetic inflammation.