Abstract

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the 'classically activated' M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, 'alternatively activated' M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data were submitted to Mendeley (DOI:10.17632/ncbph43m85.2).

The following data sets were generated

Article and author information

Author details

  1. Mimmi LE Lundahl

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    For correspondence
    lundahlm@tcd.ie
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3924-4072
  2. Morgane Mitermite

    School of Veterinary Medicine, University College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9169-2134
  3. Dylan Gerard Ryan

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  4. Sarah Case

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  5. Niamh C Williams

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  6. Ming Yang

    MRC Cancer Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Roisin I Lynch

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  8. Eimear Lagan

    School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  9. Filipa M Lebre

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  10. Aoife L Gorman

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  11. Bojan Stojkovic

    School of Veterinary Medicine, University College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  12. Adrian P Bracken

    School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  13. Christian Frezza

    MRC Cancer, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Frederick J Sheedy

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  15. Eoin M Scanlan

    School of Chemistry, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  16. Luke AJ O'Neill

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  17. Stephen V Gordon

    School of Veterinary Medicine, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  18. Ed C Lavelle

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    For correspondence
    lavellee@tcd.ie
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3167-1080

Funding

Trinity College Dublin

  • Mimmi LE Lundahl

Science Foundation Ireland (12/IA/1421)

  • Ed C Lavelle

Science Foundation Ireland (19FFP/6484)

  • Ed C Lavelle

Science Foundation Ireland (15/CDA/3310)

  • Eoin M Scanlan

Advanced Materials and Bioengineering Research (12/RC/2278_P2 E)

  • Ed C Lavelle

Science Foundation Ireland (15/IA/3154)

  • Stephen V Gordon

Wellcome Trust (109166/Z/15/A)

  • Morgane Mitermite

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animals were maintained according to the regulations of the Health Products Regulatory Authority (HPRA). Animal studies were approved by the TCD Animal Research Ethics Committee (Ethical Approval Number 091210) and were performed under the appropriate license (AE191364/P079).

Copyright

© 2022, Lundahl et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mimmi LE Lundahl
  2. Morgane Mitermite
  3. Dylan Gerard Ryan
  4. Sarah Case
  5. Niamh C Williams
  6. Ming Yang
  7. Roisin I Lynch
  8. Eimear Lagan
  9. Filipa M Lebre
  10. Aoife L Gorman
  11. Bojan Stojkovic
  12. Adrian P Bracken
  13. Christian Frezza
  14. Frederick J Sheedy
  15. Eoin M Scanlan
  16. Luke AJ O'Neill
  17. Stephen V Gordon
  18. Ed C Lavelle
(2022)
Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses
eLife 11:e74690.
https://doi.org/10.7554/eLife.74690

Share this article

https://doi.org/10.7554/eLife.74690

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