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 De 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; Claire E. McCoy

doi:10.1038/s41467-021-21617-2

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 De 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. FinlayGavin P. Davey, Tracy Robson, Annie M. Curtis, Paul J. Hertzog, Bryan R.G. Williams, Claire E. McCoy

Hudson Institute - Department of Molecular and Translational Science

Research output: Contribution to journal › Article › Research › peer-review

101 Citations (Scopus)

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.

Original language	English
Article number	1460
Number of pages	14
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21617-2
Publication status	Published - Dec 2021

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Dowling, J. K., Afzal, R., Gearing, L. J., Cervantes-Silva, M. P., Annett, S., Davis, G. M., De Santi, C., Assmann, N., Dettmer, K., Gough, D. J., Bantug, G. R., Hamid, F. I., Nally, F. K., Duffy, C. P., Gorman, A. L., Liddicoat, A. M., Lavelle, E. C., Hess, C., Oefner, P. J., ... McCoy, C. E. (2021). Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages. Nature Communications, 12(1), Article 1460. https://doi.org/10.1038/s41467-021-21617-2

@article{34efb68a15ab4e76bfd899a5f50acd97,

title = "Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages",

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.",

author = "Dowling, {Jennifer K.} and Remsha Afzal and Gearing, {Linden J.} and Cervantes-Silva, {Mariana P.} and Stephanie Annett and Davis, {Gavin M.} and {De Santi}, Chiara and Nadine Assmann and Katja Dettmer and Gough, {Daniel J.} and Bantug, {Glenn R.} and Hamid, {Fidinny I.} and Nally, {Frances K.} and Duffy, {Conor P.} and Gorman, {Aoife L.} and Liddicoat, {Alex M.} and Lavelle, {Ed C.} and Christoph Hess and Oefner, {Peter J.} and Finlay, {David K.} and Davey, {Gavin P.} and Tracy Robson and Curtis, {Annie M.} and Hertzog, {Paul J.} and Williams, {Bryan R.G.} and McCoy, {Claire E.}",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-21617-2",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

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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 2021, 'Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages', Nature Communications, vol. 12, no. 1, 1460. https://doi.org/10.1038/s41467-021-21617-2

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T1 - Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

AU - Dowling, Jennifer K.

AU - Afzal, Remsha

AU - Gearing, Linden J.

AU - Cervantes-Silva, Mariana P.

AU - Annett, Stephanie

AU - Davis, Gavin M.

AU - De Santi, Chiara

AU - Assmann, Nadine

AU - Dettmer, Katja

AU - Gough, Daniel J.

AU - Bantug, Glenn R.

AU - Hamid, Fidinny I.

AU - Nally, Frances K.

AU - Duffy, Conor P.

AU - Gorman, Aoife L.

AU - Liddicoat, Alex M.

AU - Lavelle, Ed C.

AU - Hess, Christoph

AU - Oefner, Peter J.

AU - Finlay, David K.

AU - Davey, Gavin P.

AU - Robson, Tracy

AU - Curtis, Annie M.

AU - Hertzog, Paul J.

AU - Williams, Bryan R.G.

AU - McCoy, Claire E.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-021-21617-2

DO - 10.1038/s41467-021-21617-2

M3 - Article

C2 - 33674584

AN - SCOPUS:85102200716

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1460

ER -

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

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IL-10 inhibition of miR-155 in inflammation

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

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IL-10 inhibition of miR-155 in inflammation

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