Initiation of the innate sterile inflammatory response that can develop in response to microparticle exposure is little understood. Here, we report that a potent type 2 immune response associated with the accumulation of neutrophils, eosinophils and alternatively activated (M2) macrophages was observed in response to sterile microparticles similar in size to wear debris associated with prosthetic implants. Although elevations in interleukin-33 (IL-33) and type 2 cytokines occurred independently of caspase-1 inflammasome signalling, 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 that microparticle-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.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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This work was supported by National Institutes of Health grants: R01DK11379002, R01AI13163401A1, R01AI121250, R01AI101935, RO1AI124346, RO1AR060782 and R01AI114647-01A1. We would like to acknowledge Sandvik Osprey Powders, UK for generously providing the micrometre-sized CoCr material used in this paper. In addition we would like to thank E. M. Adler, M. C. Riley, F. R. Patterson and J. S. Hwang (Department of Orthopaedic Surgery, Rutgers – New Jersey Medical School) and S. R. Peters (Department of Pathology and Laboratory Medicine, Rutgers – New Jersey Medical School) for providing clinical samples and assistance in tissue preparation.
The authors declare no competing interests.
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Mishra, P.K., Palma, M., Buechel, B. et al. Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton’s tyrosine kinase-dependent pathway. Nature Mater 18, 289–297 (2019). https://doi.org/10.1038/s41563-018-0271-6
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