Aryl hydrocarbon receptor control of a disease tolerance defence pathway (original) (raw)

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Acknowledgements

This work was supported by funding from the Italian Association for Cancer Research (AIRC, to P.P.), Fondazione Italiana Sclerosi Multipla Project No. 2010/R/17 (to F.F.), Associazione Umbra Contro il Cancro (to G.S. & M.A.D.F.), Bayer Grants4Target Focus Grant no. 2012-03-0630 (to A.I., F.F. and D.M.), Bayer Early Career Investigator Award (to D.M.), Grant no. R01ES007685 from the US National Institutes of Environmental Health Sciences (to M.S.D.), the Specific Targeted Research Project FUNMETA (to L.R.), and the Italian Ministry of Health in association with Regione dell’Umbria (GR-2008-1138004 to C.O.) We thank D. Fuchs for serum kynurenine determinations. We also thank G. Andrielli for digital art and image editing and G. Ricci for histopathology.

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Author notes

  1. Alban Bessede and Marco Gargaro: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy,
    Alban Bessede, Marco Gargaro, Maria T. Pallotta, Davide Matino, Giuseppe Servillo, Cinzia Brunacci, Carmine Vacca, Rossana Iannitti, Luciana Tissi, Claudia Volpi, Maria L. Belladonna, Ciriana Orabona, Roberta Bianchi, Maria A. Della Fazia, Danilo Piobbico, Teresa Zelante, Luigina Romani, Ursula Grohmann, Francesca Fallarino & Paolo Puccetti
  2. IMS Laboratory, University of Bordeaux, 33607 Pessac, France,
    Alban Bessede, Michel Geffard & Bernard Veyret
  3. Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy,
    Silvio Bicciato & Emilia M. C. Mazza
  4. Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy,
    Antonio Macchiarulo
  5. Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany,
    Tobias V. Lanz & Michael Platten
  6. Department of Neurooncology, University Hospital, 69120 Heidelberg, Germany,
    Tobias V. Lanz & Michael Platten
  7. Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan,
    Hiroshi Funakoshi
  8. Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan,
    Toshikazu Nakamura
  9. CNRS UMR6290, Institut de Génétique et Développement de Rennes, Université de Rennes 1, 35043 Rennes, France,
    David Gilot
  10. Department of Environmental Toxicology, University of California, Davis, 95616, California, USA
    Michael S. Denison
  11. Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia,
    Gilles J. Guillemin
  12. Lankenau Institute for Medical Research, Wynnewood, 19096, Pennsylvania, USA
    James B. DuHadaway & George C. Prendergast
  13. New Link Genetics Corporation, Ames, 50010, Iowa, USA
    Richard Metz
  14. Bioceros, 3584 Utrecht, The Netherlands,
    Louis Boon
  15. Department of Medicine, University of Perugia, 06132 Perugia, Italy,
    Matteo Pirro
  16. Department of Clinical Epidemiology & Biostatistics, McMaster University, Ontario L8S 4K1, Canada,
    Alfonso Iorio

Authors

  1. Alban Bessede
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  2. Marco Gargaro
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  3. Maria T. Pallotta
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  4. Davide Matino
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  5. Giuseppe Servillo
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  6. Cinzia Brunacci
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  7. Silvio Bicciato
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  8. Emilia M. C. Mazza
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  9. Antonio Macchiarulo
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  10. Carmine Vacca
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  11. Rossana Iannitti
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  12. Luciana Tissi
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  13. Claudia Volpi
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  14. Maria L. Belladonna
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  15. Ciriana Orabona
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  16. Roberta Bianchi
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  17. Tobias V. Lanz
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  18. Michael Platten
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  19. Maria A. Della Fazia
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  20. Danilo Piobbico
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  21. Teresa Zelante
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  22. Hiroshi Funakoshi
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  23. Toshikazu Nakamura
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  24. David Gilot
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  25. Michael S. Denison
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  26. Gilles J. Guillemin
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  27. James B. DuHadaway
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  28. George C. Prendergast
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  29. Richard Metz
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  30. Michel Geffard
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  31. Louis Boon
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  32. Matteo Pirro
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  33. Alfonso Iorio
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  34. Bernard Veyret
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  35. Luigina Romani
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  36. Ursula Grohmann
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  37. Francesca Fallarino
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  38. Paolo Puccetti
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Contributions

A.B. and M.G. designed and conducted all experiments unless otherwise indicated below; M.T.P., D.M. and C.V. analysed IDO and Src phosphorylation; S.B., E.M.C.M., D.P., M.P. and A.I. conducted bioinformatics studies and statistical analysis. A.M. performed homology modelling and docking studies. R.I., T.Z., M.A.D.F., L.R. and L.T. conducted the in vivo studies with Salmonella and GBS. C.V., M.L.B., C.O., G.S., C.B. and R.B. contributed to specific experimental designs; T.V.L., M.P., H.F. and T.N. made possible, and designed, the experiments with TDO2-deficient mice; J.B.D., G.C.P. and R.M. made possible, and designed, the experiments with IDO2-deficient mice; D.G., M.S.D., G.J.G., M.G., B.V., L.B. and U.G. provided conceptual help and reagents throughout experimentation; F.F. designed and supervised all experiments; P.P. supervised the overall study and wrote the manuscript. F.F. and P.P. share senior authorship on this paper.

Corresponding authors

Correspondence toFrancesca Fallarino or Paolo Puccetti.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Increased susceptibility to primary LPS challenge in mice treated with a TDO2 inhibitor.

a, Twelve hours before LPS challenge (10 mg per kg), WT mice were treated with vehicle, the IDO1 and IDO2 inhibitor 1-MT (200 mg per kg), or the TDO2 inhibitor 680C91 (10 mg per kg), control groups receiving 1-MT or 680C91 but no LPS. Survival was monitored every 24 h through day 8 of LPS challenge (n = 10 mice per group per experiment, in one out of three). **P < 0.001 (log-rank test). b, Estimation of LD50 (mg per kg) in mice treated with 1.25, 2.5, 5, 10, 20, 40, or 80 mg per kg LPS. n = 10 per group per dose. LD50 values were calculated by curve-fitting (_r_2 ≥ 0.95) in one experiment representative of two.

Extended Data Figure 2 Lack of endogenous IL-10 increases susceptibility to endotoxaemia.

a, Survival of WT mice exposed to 10 mg per kg LPS in the presence of anti–IL-10 (0.2 mg per mouse daily, for 4 d, commencing 6 h before challenge) or an isotype control. Data are from three independent experiments (mean ± s.d.). b, Survival of WT and _Il10_–/– mice treated with 10 mg per kg LPS. **P < 0.001 (log-rank test). c, Survival curves of mice of different genotypes challenged with 10 mg per kg LPS, with or without therapeutic subcutaneous IL-10 at 250 ng per mouse, daily, from challenge (day 0) through day 5. *P < 0.05 (IL-10 versus vehicle). The data show that exogenous IL-10 compensates for both the TDO2 and AhR defects at the lower LPS dosage. IL-10 is protective only in TDO2 knockouts when 20 mg per kg LPS is used.

Extended Data Figure 3 Mutation of Gln 377 to Ala in AhR PAS-B domain does not alter receptor half-life, and apparently results in increased TCDD ligand potency.

a, AhR-deficient cDCs were transfected with WT or AhR(Q377A). After 24 h, cells were incubated with cycloheximide (CXM) (10 µg ml−1) and harvested at different times, lysed, and analysed for AhR expression by immunoblotting, using a specific antibody. β-tubulin was used as a loading control. Data are from one experiment of three. b, Ratios (means ± s.d. of three experiments) of WT or AhR(Q377A) to β-tubulin in transfected cDCs at different times of CHX treatment. (No differences by Student’s _t_-test.)

Extended Data Figure 4 LPS tolerance potentiates IDO1 expression and AhR activation in splenic cDCs.

a, b, Real-time PCR analysis of Ido1 mRNA expression and immunoblot analysis of IDO1 protein in peritoneal exudate macrophages (MΦ) and neutrophils (Neu) (a), as well as in splenic conventional DCs (cDCs) or plasmacytoid DCs (pDCs) (b). Cells were harvested and purified at 24 h (a) or 72 h (b) of LPS rechallenge. For comparison, samples were included from mice on first exposure to 40 mg per kg LPS (unprimed), as opposed to tolerized mice (primed). Data of Ido1 mRNA fold induction are presented as means ± s.d. of three experiments; *P < 0.05 and **P < 0.001, Shapiro test. Immunoblotting data are from one experiment of three. c, Real-time PCR analysis of Ahr and Cyp1a1 transcript expressions in cDCs from the same mice as in b. **P < 0.001, Shapiro test.

Extended Data Figure 5 Absolute requirement for functional AhR, but not TDO2, in LPS tolerance manifestations.

a, Survival curves of WT and LPS-primed (0.5 mg per kg, day 0) WT (prWT) and AhR-deficient (pr_Ahr_–/–) mice after a second challenge (on day +7) with 40 mg per kg LPS. Survival was monitored every 24 h through day 8 of LPS challenge. n = 8–10 mice per group per experiment. One experiment of three. *P < 0.05, log-rank test. b, Survival curves of WT and LPS-primed (10 mg per kg, day 0) WT (prWT) and TDO2-deficient (pr_Tdo2_–/–) mice after a second challenge (on day +7) with 40 mg per kg LPS. Survival was monitored every 24 h through day 8 of LPS challenge. n = 8–10 mice per group per experiment. One experiment of three. **P < 0.001, log-rank test.

Extended Data Figure 6 Bioinformatic data from myeloid cDCs data sets.

a, Expression changes of tyrosine kinases in LPS-primed myeloid DCs compared to untreated counterparts. b, Log2 fold changes, depicted as mean values and standard errors.

Extended Data Figure 7 LPS tolerance modulates cytokine production and Foxp3 and Rorc transcription in S. Typhimurium infection.

a, IL-6, IL-1β, TNF-α, IL-10, and TGF-β were measured in caecum cell supernatants from LPS-tolerant mice infected with S. enterica Typhimurium. Data are from three independent experiments (means ± s.d.). *P < 0.05 and **P < 0.001 (Student’s _t_-test). b, RT–PCR expression of Foxp3 and Rorc transcripts in mesenteric lymph node cells from LPS-tolerant, _Salmonella_-infected mice. Data (mean ± s.d. of three experiments) are presented as normalized transcript expression in the samples relative to normalized transcript expression in control cultures (that is, cells from vehicle-treated mice, in which fold change = 1; dotted line). *P < 0.05; **P < 0.001 (Shapiro test).

Extended Data Figure 8 _Ahr_–/– and _Ido_–/– mice are more susceptible than WT mice to S. Typhimurium infection.

a, Naive mice of different genotypes were challenged intragastrically with S. Typhimurium. Mortality data were recorded (**P < 0.001, WT versus all other genotypes; log-rank test). b, Haematoxylin and eosin staining of mouse caeca was performed at 7 days of infection. Scale bars, 50 μm. One of three experiments. c, Transcript expressions of Il17a, Rorc, Il10, and Foxp3 were quantified in mesenteric lymph node cells. Data (mean ± s.d. of three experiments) are presented as normalized transcript expression in the samples relative to normalized transcript expression in cells from uninfected donors, in which fold change = 1. **P < 0.001 (Shapiro test).

Extended Data Figure 9 LPS tolerance modulates Foxp3 and Rorc transcription in GBS infection.

RT–PCR expression of Foxp3 and Rorc transcripts in joint-draining lymph node cells from LPS-tolerant, GBS-infected mice. Data (mean ± s.d. of three experiments) are presented as normalized transcript expression in the samples relative to normalized transcript expression in control cells (that is, cells from vehicle-treated mice, in which fold change = 1; dotted line). **P < 0.001 (Shapiro test).

Extended Data Figure 10 _Ahr_–/– and _Ido_–/– mice are more susceptible than WT mice to GBS immunopathology.

a, Naive mice of different genotypes were infected with GBS (107 c.f.u.). Mortality data were recorded (*P < 0.05 and **P < 0.001, WT versus all other genotypes; log-rank test). b, Haematoxylin and eosin staining of joints was performed at 10 days of infection. Scale bars, 100 μm. One of three experiments. c, Transcript expressions of Il17a, Rorc, Il10, and Foxp3 were quantified in joint-draining lymph nodes. Data (mean ± s.d. of three experiments) are presented as normalized transcript expression in the samples relative to normalized transcript expression in cells from uninfected donors, in which fold change = 1. **P < 0.001 (Shapiro test).

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Bessede, A., Gargaro, M., Pallotta, M. et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway.Nature 511, 184–190 (2014). https://doi.org/10.1038/nature13323

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