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Sulforaphane prevents and reverses allergic airways disease in mice via anti-inflammatory, antioxidant, and epigenetic mechanisms

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Abstract

Sulforaphane has been investigated in human pathologies and preclinical models of airway diseases. To provide further mechanistic insights, we explored L-sulforaphane (LSF) in the ovalbumin (OVA)-induced chronic allergic airways murine model, with key hallmarks of asthma. Histological analysis indicated that LSF prevented or reversed OVA-induced epithelial thickening, collagen deposition, goblet cell metaplasia, and inflammation. Well-known antioxidant and anti-inflammatory mechanisms contribute to the beneficial effects of LSF. Fourier transform infrared microspectroscopy revealed altered composition of macromolecules, following OVA sensitization, which were restored by LSF. RNA sequencing in human peripheral blood mononuclear cells highlighted the anti-inflammatory signature of LSF. Findings indicated that LSF may alter gene expression via an epigenetic mechanism which involves regulation of protein acetylation status. LSF resulted in histone and α-tubulin hyperacetylation in vivo, and cellular and enzymatic assays indicated decreased expression and modest histone deacetylase (HDAC) inhibition activity, in comparison with the well-known pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Molecular modeling confirmed interaction of LSF and LSF metabolites with the catalytic domain of metal-dependent HDAC enzymes. More generally, this study confirmed known mechanisms and identified potential epigenetic pathways accounting for the protective effects and provide support for the potential clinical utility of LSF in allergic airways disease.

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Data and materials availability

RNA sequencing data are available from GEO under the accession GSE160353. To review GEO accession GSE160353 while it remains in private status, go the following address and enter the access token: otmlcuoillwhjcd. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE160353

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Acknowledgements

We acknowledge the intellectual and financial support from McCord Research (Iowa, USA). The authors would like to acknowledge the use of the facilities provided by Monash University (Clayton, VIC, Australia) and the Murdoch Children’s Research Institute (Parkville, VIC, Australia) for their care and husbandry of the mice. The Gomori’s aldehyde-fuchsin and silver impregnation stains were performed by Ms Laura Leone at the Melbourne University Histology Platform (University of Melbourne, School of Biomedical Sciences, Parkville, VIC, Australia). The authors would like to acknowledge the use of the facilities provided by Monash Micro Imaging (MMI) at the Alfred Research Alliance (ARA, Melbourne, VIC, Australia) and, particularly, the expert assistance from Drs Stephen Cody and Iśka Carmichael. FPA-FTIR imaging measurements were undertaken at the IRM beamline at the Australian Synchrotron, part of ANSTO (Clayton, VIC, Australia). Various figures in this manuscript were created with BioRender.com. We thank the National Computing Infrastructure (NCI), and the Pawsey Supercomputing Centre in Australia (funded by the Australian Government). Further, we thank the Spartan High Performance Computing service (University of Melbourne), and the Partnership for Advanced Computing in Europe (PRACE) for awarding the access to Piz Daint, hosted at the Swiss National Supercomputing Centre (CSCS), Switzerland. We acknowledge our use of the gene set enrichment analysis, GSEA software, and Molecular Signature Database (MSigDB) (Subramanian, Tamayo, et al. (2005), PNAS 102, 15545-15550, http://www.broad.mit.edu/gsea/).

Funding

We would like to acknowledge intellectual and financial support by McCord Research (Iowa, USA). AEO is supported by an National Health and Medical Research Council (NHMRC) Senior Research Fellowship (1154650). PVL is supported by an NHMRC Career Development Fellowship (1146198). CD is supported by an NHMRC Early Career Postdoctoral Fellowship (1120152). JJL is supported by an Australian Government Research Training Program Scholarship.

Author information

Authors and Affiliations

  1. Epigenomic Medicine Laboratory, Department of Diabetes, Central Clinical School, Monash University, Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia

    Simon G. Royce, Raymond C. Beh, Julia J. Liang, Nadia Mazarakis, Eleni Pitsillou, Ya Yun Siow, Katherine Ververis & Tom C. Karagiannis

  2. Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia

    Simon G. Royce, Raymond C. Beh, Katherine Ververis & Tom C. Karagiannis

  3. Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia

    Simon G. Royce & Jane E. Bourke

  4. Infection and Immunity, Murdoch Children’s Research Institute, Melbourne, VIC, 3052, Australia

    Simon G. Royce, Paul V. Licciardi & Nadia Mazarakis

  5. Department of Paediatrics, The University of Melbourne, Melbourne, VIC, 3010, Australia

    Paul V. Licciardi, Nadia Mazarakis & Mimi L. K. Tang

  6. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, 2305, Australia

    Chantal Donovan

  7. Centre for Inflammation, Centenary Institute, Camperdown, NSW, 2050, Australia

    Chantal Donovan

  8. School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia

    Chantal Donovan

  9. School of Science, STEM College, RMIT University, VIC, 3001, Australia

    Andrew Hung, Julia J. Liang & Eleni Pitsillou

  10. Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Monash University, Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia

    Ishant Khurana, Scott Maxwell, Mark Ziemann & Assam El-Osta

  11. Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC, 3010, Australia

    Nadia Mazarakis & Kenneth J. Snibson

  12. ANSTO-Australian Synchrotron, Clayton, VIC, 3168, Australia

    Mark J. Tobin & Jitraporn Vongsvivut

  13. School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Warrnambool, VIC, 3216, Australia

    Mark Ziemann

  14. Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia

    Chrishan S. Samuel

  15. Population Allergy Group, Murdoch Children’s Research Institute, Parkville, VIC, 3052, Australia

    Mimi L. K. Tang

  16. Department of Allergy and Immunology, Royal Children’s Hospital, Parkville, VIC, 3052, Australia

    Mimi L. K. Tang

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  1. Simon G. Royce
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  2. Paul V. Licciardi
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  3. Raymond C. Beh
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Contributions

SGR, JEB, AH, PVL, CSS, KJS, MLKT, AE, and TCK conceptualized the ideas and overarching aims. JEB, AH, PVL, CSS, KJS, MJT, JV, MLKT, AE, and TCK were involved in supervision. KV, CD, AH, IK, JJL, SM, NM, EP, MJT, JV, and MZ participated in the development and design of the methodology. KV, CD, IK, SM, NM, MJT, JV, and MZ conducted the research and investigation process. RCB, AH, JJL, EP, YYS, and MZ were responsible for visualization and KV, EP, SGR, PVL, and TCK were involved in production of the first draft of the manuscript.

Corresponding author

Correspondence to Tom C. Karagiannis.

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Competing interests

Epigenomic Medicine Program (TCK) was supported financially by McCord Research (Iowa, USA), which has a financial interest in dietary compounds including sulforaphane. The remaining co-authors declare that they have no direct financial relation with the commercial identities mentioned in this manuscript that might lead to a conflict of interest.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Six-week-old female BALB/c mice were obtained from Walter and Eliza Hall Institute Bioservices (prevention model; Parkville, VIC, Australia) and Monash Animal Services (reversal model; Clayton, VIC, Australia). The prevention model experimental protocol was approved by the Murdoch Children’s Research Institute Animal Ethics Committee (approval no. A597). The reversal model experimental protocol was approved by the Monash University Animal Ethics Committee (MARP/2012/085). All experimental procedures followed the Australian guidelines for the care and use of laboratory animals for scientific purposes. Human peripheral blood mononuclear cells (PBMC) were fractionated using Ficoll Paque (GE Healthcare, Wauwatosa, Wisconsin, USA) from blood samples (healthy participants; n = 4) obtained from the Australian Red Cross Blood Bank (Melbourne, VIC, Australia) under ethics project (#304/12) approved by the Alfred Hospital Ethics Committee (Alfred Health, Melbourne, VIC, Australia). Human epithelial lung A549 cells were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA).

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Royce, S.G., Licciardi, P.V., Beh, R.C. et al. Sulforaphane prevents and reverses allergic airways disease in mice via anti-inflammatory, antioxidant, and epigenetic mechanisms. Cell. Mol. Life Sci. 79, 579 (2022). https://doi.org/10.1007/s00018-022-04609-3

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  • DOI: https://doi.org/10.1007/s00018-022-04609-3

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