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Abstract

The incidences of chronic inflammatory disorders have increased considerably over the past three decades1. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2cmo mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans2,3,4. Recent reports demonstrated a crucial role for interleukin-1β (IL-1β) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2cmo mice from inflammatory bone disease5,6. Thus, the upstream mechanisms controlling IL-1β production in Pstpip2cmo mice remain to be identified. In addition, the environmental factors driving IL-1β-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2cmo mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2cmo mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1β expression in distant neutrophils. Furthermore, pro-IL-1β expression was also decreased in Pstpip2cmo mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1β-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1β and osteomyelitis in Pstpip2cmo mice.

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Acknowledgements

We thank D. Chaplin, V. Dixit, R. Flavell, D. Green and C. Pham for the supply of mutant mice. We thank J. Kim for helping to acquire and analyse the micro-computed tomography data. We thank S. Olsen, D. Roeber and the Genome Sequencing Facility in the Hartwell Center at St Jude Children’s Research Hospital for performing metagenomics sequencing of 16S rRNA. M.L. is supported by grants from Ghent University (BOF 01N02313 and 01J11113) and the European Research Council (Grant 281600). L.V.W. is a postdoctoral fellow of the Fund for Scientific Research-Flanders. This work was supported by: the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award Number AR056296 (T.-D.K.); the National Cancer Institute, part of the National Institutes of Health, under Award Number CA163507 (T.-D.K.); the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under Award Number AI101935 (T.-D.K.); and ALSAC.

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Affiliations

  1. Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • John R. Lukens
    • , Prajwal Gurung
    • , Gordon R. Johnson
    • , Srinivasa Rao Bandi
    •  & Thirumala-Devi Kanneganti
  2. Animal Resources Center and the Veterinary Pathology Core, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Peter Vogel
  3. Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Robert A. Carter
    •  & Daniel J. McGoldrick
  4. Small Animal Imaging Core, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Christopher R. Calabrese
  5. Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium

    • Lieselotte Vande Walle
    •  & Mohamed Lamkanfi
  6. Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium

    • Lieselotte Vande Walle
    •  & Mohamed Lamkanfi

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Contributions

J.R.L., M.L. and T.-D.K. designed the study; J.R.L., P.G., L.V.W., C.R.C. and S.R.B. performed experiments, and G.R.J. provided technical assistance. D.J.M. and R.A.C. analysed the 16S rRNA metagenomics data, and P.V. performed and analysed the histopathology data. J.R.L., M.L. and T.-D.K. analysed data and wrote the manuscript; T.-D.K. oversaw the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thirumala-Devi Kanneganti.

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https://doi.org/10.1038/nature13788

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