Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton’s tyrosine kinase-dependent pathway

Abstract

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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Fig. 1: The MP-induced type 2 innate response is BTK dependent.
Fig. 2: Macrophages produce IL-33 and IL-33 blockade inhibits the type 2 response.
Fig. 3: IL-33 restores the response after BTK inhibition.
Fig. 4: Macrophages rescue type 2 inflammation in BTK-deficient mice.
Fig. 5: MP-induced articular tissue inflammation is SYK, BTK and IL33 dependent.
Fig. 6: Increased M2 macrophage markers detected in periprosthetic tissues.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

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.

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W.C.G., P.K.M., M.P. and K.S.B. designed the experiments. P.K.M. and M.P. conducted all the experiments. B.B. and J.M. helped in collecting and processing of tissue biopsies from human clinical samples and A.M. provided technical assistance with immune staining. N.J.H. determined the sizes of wear debris particles and helped in particle separation. T.-D.K. provided caspase1-/- mice and technical suggestions for the experiments. K.S.B. and J.B. coordinated the clinical studies with human subjects. V.D. and R.B.B. provided technical assistance and advice in experiments assessing macrophage death and phagocytosis. N.C. and E.M.B. provided ST2-/- mice, laboratory assistance and suggestions for the experiments. A.R. provided the CCR2 reporter mice and associated technical assistance. W.C.G., P.K.M. and M.P. wrote the manuscript.

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Correspondence to William C. Gause.

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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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