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

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. Bantug, Fidinny I. Hamid, Frances K. Nally, Conor P. Duffy, Aoife L. Gorman, Alex M. Liddicoat, Ed C. Lavelle, Christoph Hess, Peter J. Oefner, David K. Finlay, Gavin P. Davey, Tracy Robson, Annie M. Curtis, Paul J. Hertzog, Bryan R. G. Williams and Claire E. McCoy ()
Additional contact information
Jennifer K. Dowling: Royal College of Surgeons in Ireland
Remsha Afzal: Royal College of Surgeons in Ireland
Linden J. Gearing: Hudson Institute of Medical Research
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
Katja Dettmer: University of Regensburg
Daniel J. Gough: Monash University
Glenn R. Bantug: University Hospital Basel
Fidinny I. Hamid: Monash University
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
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
Bryan R. G. Williams: Monash University
Claire E. McCoy: Royal College of Surgeons in Ireland

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21617-2

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