Mitochondrial arginase-2 is essential....pdf (3 MB)

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

Download (3 MB)
journal contribution
posted on 24.05.2021, 09:19 by Jennifer DowlingJennifer Dowling, Remsha AfzalRemsha Afzal, Linden J Gearing, Mariana Patricia Cervantes Silva, Stephanie Annett, Gavin M Davis, Chiara De SantiChiara De Santi, Nadine Assmann, Katja Dettmer, Daniel J Gough, Glenn R Bantug, Fidinny I Hamid, Frances NallyFrances Nally, Conor DuffyConor Duffy, Aoife L Gorman, Alex M Liddicoat, Ed C Lavelle, Christoph Hess, Peter J Oefner, David K Finlay, Gavin P Davey, Tracy RobsonTracy Robson, Annie CurtisAnnie Curtis, Paul J. Hertzog, Bryan RG Williams, Claire McCoyClaire McCoy
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.

Funding

Impact of circadian control in mitochondrial metabolism in Dendritic Cells and their implications in vaccination. | Funder: The National Council of Science and Technology (CONACYT | Grant ID: The National Council of Science and Technology (CONACYT

Science Foundation Ireland (SFI16/FRL/3855)

National Health and Medical Research Council Australia (APP1063400)

CONACYT (CVU440823)

Science Foundation Ireland Career Development Award (17/CDA/4688)

ERC-CoG (770769 DC_Nutrient)

Swiss National Science Foundation (SNSF31003A_172848)

Children’s Cancer Foundation

Irish Research Council (GOIPD/2018/575 and GOIPG/2018/2648)

Science Foundation Ireland (SFI12/IA/1421)

Irish Research Council (GOIPG/ 2015/4023) and EPSPG/2017/302

National Children’s Research Centre (C/18/9)

Victoria Cancer Agency Mid-Career Fellowship (MCRF19033)

History

Associated research data files

The gene expression datasets generated by the Affymetrix array have been deposited in GSE under accession code GSE151835. Other data are available in the article and supplementary information files.

Comments

The original article is available at https://www.nature.com

Published Citation

Dowling JK, Afzal R, Gearing LJ, Cervantes-Silva MP, Annett S, Davis GM, De Santi C, Assmann N, Dettmer K, Gough DJ, Bantug GR, Hamid FI, Nally FK, Duffy CP, Gorman AL, Liddicoat AM, Lavelle EC, Hess C, Oefner PJ, Finlay DK, Davey GP, Robson T, Curtis AM, Hertzog PJ, Williams BRG, McCoy CE. Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages. Nature Communications. 2021;12(1):1460.

Publication Date

5 March 2021

PubMed ID

33674584

Department/Unit

  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Biomaterials and Regenerative Medicine
  • Cancer
  • Health Professions Education
  • Vascular Biology
  • Immunity, Infection and Inflammation
  • Respiratory Medicine

Publisher

Springer Nature

Version

  • Published Version (Version of Record)