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Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

Author

Listed:
  • Jennifer K. Dowling

    (Royal College of Surgeons in Ireland
    Hudson Institute of Medical Research
    SFI Research Centre
    Monash University)

  • Remsha Afzal

    (Royal College of Surgeons in Ireland)

  • Linden J. Gearing

    (Hudson Institute of Medical Research
    Monash University)

  • Mariana P. Cervantes-Silva

    (Royal College of Surgeons in Ireland)

  • Stephanie Annett

    (Royal College of Surgeons in Ireland)

  • Gavin M. Davis

    (Trinity College Dublin)

  • Chiara Santi

    (Royal College of Surgeons in Ireland)

  • Nadine Assmann

    (Trinity College Dublin
    University Hospital Basel)

  • Katja Dettmer

    (University of Regensburg)

  • Daniel J. Gough

    (Monash University
    Hudson Institute of Medical Research)

  • Glenn R. Bantug

    (University Hospital Basel
    University of Cambridge)

  • Fidinny I. Hamid

    (Monash University
    Hudson Institute of Medical Research)

  • Frances K. Nally

    (Royal College of Surgeons in Ireland)

  • Conor P. Duffy

    (Royal College of Surgeons in Ireland)

  • Aoife L. Gorman

    (Trinity College Dublin)

  • Alex M. Liddicoat

    (Trinity College Dublin)

  • Ed C. Lavelle

    (Trinity College Dublin)

  • Christoph Hess

    (University Hospital Basel
    University of Cambridge)

  • Peter J. Oefner

    (University of Regensburg)

  • David K. Finlay

    (Trinity College Dublin)

  • Gavin P. Davey

    (Trinity College Dublin)

  • Tracy Robson

    (Royal College of Surgeons in Ireland)

  • Annie M. Curtis

    (Royal College of Surgeons in Ireland)

  • Paul J. Hertzog

    (Hudson Institute of Medical Research
    Monash University)

  • Bryan R. G. Williams

    (Monash University
    Hudson Institute of Medical Research)

  • Claire E. McCoy

    (Royal College of Surgeons in Ireland
    SFI Research Centre
    Monash University
    Hudson Institute of Medical Research)

Abstract

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

Suggested Citation

  • Jennifer K. Dowling & Remsha Afzal & Linden J. Gearing & Mariana P. Cervantes-Silva & Stephanie Annett & Gavin M. Davis & Chiara Santi & Nadine Assmann & Katja Dettmer & Daniel J. Gough & Glenn R. Ban, 2021. "Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21617-2
    DOI: 10.1038/s41467-021-21617-2
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