Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis

Pranvera Sadiku; Joseph A. Willson; Eilise M. Ryan; David Sammut; Patricia Coelho; Emily R. Watts; Robert Grecian; Jason M. Young; Martin Bewley; Simone Arienti; Ananda S. Mirchandani; Manuel A. Sanchez Garcia; Tyler Morrison; Ailing Zhang; Leila Reyes; Tobias Griessler; Privjyot Jheeta; Gordon G. Paterson; Christopher J. Graham; John P. Thomson; Kenneth Baillie; A. A.Roger Thompson; Jessie May Morgan; Abel Acosta-Sanchez; Veronica M. Dardé; Jordi Duran; Joan J. Guinovart; Gio Rodriguez-Blanco; Alex Von Kriegsheim; Richard R. Meehan; Massimiliano Mazzone; David H. Dockrell; Bart Ghesquiere; Peter Carmeliet; Moira K.B. Whyte; Sarah R. Walmsley

doi:10.1016/j.cmet.2020.11.016

Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis

Pranvera Sadiku
, Joseph A. Willson
, Eilise M. Ryan
, David Sammut
, Patricia Coelho
, Emily R. Watts
, Robert Grecian
, Jason M. Young
, Martin Bewley
, Simone Arienti
, Ananda S. Mirchandani
, Manuel A. Sanchez Garcia
, Tyler Morrison
, Ailing Zhang
, Leila Reyes
, Tobias Griessler
, Privjyot Jheeta
, Gordon G. Paterson
, Christopher J. Graham
, John P. Thomson

Kenneth Baillie, A. A.Roger Thompson, Jessie May Morgan, Abel Acosta-Sanchez, Veronica M. Dardé, Jordi Duran, Joan J. Guinovart, Gio Rodriguez-Blanco, Alex Von Kriegsheim, Richard R. Meehan, Massimiliano Mazzone, David H. Dockrell, Bart Ghesquiere, Peter Carmeliet, Moira K.B. Whyte, Sarah R. Walmsley^*

^*Corresponding author for this work

Research output: Indexed journal article › Article › peer-review

190 Citations (Web of Science)

Abstract

Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-¹³C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.

Original language	English
Pages (from-to)	411-423.e4
Journal	Cell Metabolism
Volume	33
Issue number	2
Early online date	10 Dec 2020
DOIs	https://doi.org/10.1016/j.cmet.2020.11.016
Publication status	Published - 2 Feb 2021
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

COPD
GYS1
gluconeogenesis
glycogen
glycogenesis
glycogenolysis
glycolysis
inflammation
neutrophil

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10.1016/j.cmet.2020.11.016Licence: CC BY

Cite this

Sadiku, P., Willson, J. A., Ryan, E. M., Sammut, D., Coelho, P., Watts, E. R., Grecian, R., Young, J. M., Bewley, M., Arienti, S., Mirchandani, A. S., Sanchez Garcia, M. A., Morrison, T., Zhang, A., Reyes, L., Griessler, T., Jheeta, P., Paterson, G. G., Graham, C. J., ... Walmsley, S. R. (2021). Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis. Cell Metabolism, 33(2), 411-423.e4. https://doi.org/10.1016/j.cmet.2020.11.016

@article{cfa6a577cc0242f0a7f9507dc8491ec4,

title = "Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis",

abstract = "Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.",

keywords = "COPD, GYS1, gluconeogenesis, glycogen, glycogenesis, glycogenolysis, glycolysis, inflammation, neutrophil",

author = "Pranvera Sadiku and Willson, \{Joseph A.\} and Ryan, \{Eilise M.\} and David Sammut and Patricia Coelho and Watts, \{Emily R.\} and Robert Grecian and Young, \{Jason M.\} and Martin Bewley and Simone Arienti and Mirchandani, \{Ananda S.\} and \{Sanchez Garcia\}, \{Manuel A.\} and Tyler Morrison and Ailing Zhang and Leila Reyes and Tobias Griessler and Privjyot Jheeta and Paterson, \{Gordon G.\} and Graham, \{Christopher J.\} and Thomson, \{John P.\} and Kenneth Baillie and Thompson, \{A. A.Roger\} and Morgan, \{Jessie May\} and Abel Acosta-Sanchez and Dard{\'e}, \{Veronica M.\} and Jordi Duran and Guinovart, \{Joan J.\} and Gio Rodriguez-Blanco and \{Von Kriegsheim\}, Alex and Meehan, \{Richard R.\} and Massimiliano Mazzone and Dockrell, \{David H.\} and Bart Ghesquiere and Peter Carmeliet and Whyte, \{Moira K.B.\} and Walmsley, \{Sarah R.\}",

note = "Funding Information: We thank Sandra Schoors for providing guidance and help with the radioactive assays, Wesley Vermaelen and Camila Takeno Cologna for help with LC-MS analysis, and the QMRI Flow Cytometry Facility for help with flow cytometry. This work was principally supported by Wellcome Trust Clinical Fellowship awards, UK ( 098516 and 209220 to S.R.W.). The work of P. Carmeliet is supported by long-term structural Methusalem funding from the Flemish Government. The Apex 5 expedition was supported by funding from the JABBS and Sylvia Waddilove Foundations, UK. Work in R.R.M.{\textquoteright}s lab is supported by Medical Research Council (MC\_PC\_U127574433 and MC\_UU\_0007/17), UK. Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2021",

month = feb,

day = "2",

doi = "10.1016/j.cmet.2020.11.016",

language = "English",

volume = "33",

pages = "411--423.e4",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "2",

}

Sadiku, P, Willson, JA, Ryan, EM, Sammut, D, Coelho, P, Watts, ER, Grecian, R, Young, JM, Bewley, M, Arienti, S, Mirchandani, AS, Sanchez Garcia, MA, Morrison, T, Zhang, A, Reyes, L, Griessler, T, Jheeta, P, Paterson, GG, Graham, CJ, Thomson, JP, Baillie, K, Thompson, AAR, Morgan, JM, Acosta-Sanchez, A, Dardé, VM, Duran, J, Guinovart, JJ, Rodriguez-Blanco, G, Von Kriegsheim, A, Meehan, RR, Mazzone, M, Dockrell, DH, Ghesquiere, B, Carmeliet, P, Whyte, MKB & Walmsley, SR 2021, 'Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis', Cell Metabolism, vol. 33, no. 2, pp. 411-423.e4. https://doi.org/10.1016/j.cmet.2020.11.016

TY - JOUR

T1 - Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis

AU - Sadiku, Pranvera

AU - Willson, Joseph A.

AU - Ryan, Eilise M.

AU - Sammut, David

AU - Coelho, Patricia

AU - Watts, Emily R.

AU - Grecian, Robert

AU - Young, Jason M.

AU - Bewley, Martin

AU - Arienti, Simone

AU - Mirchandani, Ananda S.

AU - Sanchez Garcia, Manuel A.

AU - Morrison, Tyler

AU - Zhang, Ailing

AU - Reyes, Leila

AU - Griessler, Tobias

AU - Jheeta, Privjyot

AU - Paterson, Gordon G.

AU - Graham, Christopher J.

AU - Thomson, John P.

AU - Baillie, Kenneth

AU - Thompson, A. A.Roger

AU - Morgan, Jessie May

AU - Acosta-Sanchez, Abel

AU - Dardé, Veronica M.

AU - Duran, Jordi

AU - Guinovart, Joan J.

AU - Rodriguez-Blanco, Gio

AU - Von Kriegsheim, Alex

AU - Meehan, Richard R.

AU - Mazzone, Massimiliano

AU - Dockrell, David H.

AU - Ghesquiere, Bart

AU - Carmeliet, Peter

AU - Whyte, Moira K.B.

AU - Walmsley, Sarah R.

N1 - Funding Information: We thank Sandra Schoors for providing guidance and help with the radioactive assays, Wesley Vermaelen and Camila Takeno Cologna for help with LC-MS analysis, and the QMRI Flow Cytometry Facility for help with flow cytometry. This work was principally supported by Wellcome Trust Clinical Fellowship awards, UK ( 098516 and 209220 to S.R.W.). The work of P. Carmeliet is supported by long-term structural Methusalem funding from the Flemish Government. The Apex 5 expedition was supported by funding from the JABBS and Sylvia Waddilove Foundations, UK. Work in R.R.M.’s lab is supported by Medical Research Council (MC_PC_U127574433 and MC_UU_0007/17), UK. Publisher Copyright: © 2020 The Authors

PY - 2021/2/2

Y1 - 2021/2/2

N2 - Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.

AB - Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.

KW - COPD

KW - GYS1

KW - gluconeogenesis

KW - glycogen

KW - glycogenesis

KW - glycogenolysis

KW - glycolysis

KW - inflammation

KW - neutrophil

UR - https://www.scopus.com/pages/publications/85098506510

UR - https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;KeyUT=000632621300003

U2 - 10.1016/j.cmet.2020.11.016

DO - 10.1016/j.cmet.2020.11.016

M3 - Article

C2 - 33306983

AN - SCOPUS:85098506510

SN - 1550-4131

VL - 33

SP - 411-423.e4

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis

Abstract

UN SDGs

Keywords

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