Lactate supports a metabolic-epigenetic link in macrophage polarization

Jordan T. Noe; Beatriz E. Rendon; Anne E. Geller; Lindsey R. Conroy; Samantha M. Morrissey; Lyndsay E.A. Young; Ronald C. Bruntz; Eun J. Kim; Ashley Wise-Mitchell; Mariana Barbosa De Souza Rizzo; Eric R. Relich; Becca V. Baby; Lance A. Johnson; Hayley C. Affronti; Kelly M. McMasters; Brian F. Clem; Matthew S. Gentry; Jun Yan; Kathryn E. Wellen; Ramon C. Sun; Robert A. Mitchell

doi:10.1126/sciadv.abi8602

Lactate supports a metabolic-epigenetic link in macrophage polarization

Jordan T. Noe, Beatriz E. Rendon, Anne E. Geller, Lindsey R. Conroy, Samantha M. Morrissey, Lyndsay E.A. Young, Ronald C. Bruntz, Eun J. Kim, Ashley Wise-Mitchell, Mariana Barbosa De Souza Rizzo, Eric R. Relich, Becca V. Baby, Lance A. Johnson, Hayley C. Affronti, Kelly M. McMasters, Brian F. Clem, Matthew S. Gentry, Jun Yan, Kathryn E. Wellen, Ramon C. SunRobert A. Mitchell

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

181 Scopus citations

Abstract

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)-induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate- citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage-dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)-driven metabolic-epigenetic link in M2 macrophages.

Original language	English
Article number	eabi8602
Journal	Science advances
Volume	7
Issue number	46
DOIs	https://doi.org/10.1126/sciadv.abi8602
State	Published - Nov 2021

Bibliographical note

Publisher Copyright:
Copyright © 2021 The Authors.

Funding

This work was supported by National Institutes of Health (NIH) Predoctoral Fellowship Award F30CA232550 (to J.T.N.), NIH Pre- to Postdoctoral Transition Award 4K00CA212455 (to H.C.A.), NIH Research Grant R35NS116824 (to M.S.G.), NIH Research Grant R01AG060056 (to L.A.J.), NIH Research Grant R01AG062550 (to L.A.J.), NIH Research Grant R01CA213990 (to J.Y.), NIH Research Grant R01DK116005 (to K.E.W.), NIH Research Grant R01CA174761 (to K.E.W.), NIH Research Grant R01AG066653 (to R.C.S.), V Scholar Grant (to R.C.S.), NIH Research Grant R01CA186661 (to R.A.M.), NIH Research Grant GB130096P3 (to R.A.M.), and NIH Project Grant P20GM135004 (to J.Y. and R.A.M.).

Funders	Funder number
National Institutes of Health (NIH)	R01AG062550, R01CA174761, R01DK116005, R35NS116824, P20GM135004, F30CA232550, R01AG066653, R01CA186661, R01CA213990, R01AG060056, GB130096P3
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	K00CA212455
National Childhood Cancer Registry – National Cancer Institute

ASJC Scopus subject areas

General

UN SDGs

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

Access to Document

10.1126/sciadv.abi8602

Cite this

Noe, J. T., Rendon, B. E., Geller, A. E., Conroy, L. R., Morrissey, S. M., Young, L. E. A., Bruntz, R. C., Kim, E. J., Wise-Mitchell, A., De Souza Rizzo, M. B., Relich, E. R., Baby, B. V., Johnson, L. A., Affronti, H. C., McMasters, K. M., Clem, B. F., Gentry, M. S., Yan, J., Wellen, K. E., ... Mitchell, R. A. (2021). Lactate supports a metabolic-epigenetic link in macrophage polarization. Science advances, 7(46), Article eabi8602. https://doi.org/10.1126/sciadv.abi8602

@article{a273654edb044db68fb6d2c576f8079d,

title = "Lactate supports a metabolic-epigenetic link in macrophage polarization",

abstract = "Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)-induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate- citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage-dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)-driven metabolic-epigenetic link in M2 macrophages.",

author = "Noe, \{Jordan T.\} and Rendon, \{Beatriz E.\} and Geller, \{Anne E.\} and Conroy, \{Lindsey R.\} and Morrissey, \{Samantha M.\} and Young, \{Lyndsay E.A.\} and Bruntz, \{Ronald C.\} and Kim, \{Eun J.\} and Ashley Wise-Mitchell and \{De Souza Rizzo\}, \{Mariana Barbosa\} and Relich, \{Eric R.\} and Baby, \{Becca V.\} and Johnson, \{Lance A.\} and Affronti, \{Hayley C.\} and McMasters, \{Kelly M.\} and Clem, \{Brian F.\} and Gentry, \{Matthew S.\} and Jun Yan and Wellen, \{Kathryn E.\} and Sun, \{Ramon C.\} and Mitchell, \{Robert A.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors.",

year = "2021",

month = nov,

doi = "10.1126/sciadv.abi8602",

language = "English",

volume = "7",

number = "46",

}

Noe, JT, Rendon, BE, Geller, AE, Conroy, LR, Morrissey, SM, Young, LEA, Bruntz, RC, Kim, EJ, Wise-Mitchell, A, De Souza Rizzo, MB, Relich, ER, Baby, BV, Johnson, LA, Affronti, HC, McMasters, KM, Clem, BF, Gentry, MS, Yan, J, Wellen, KE, Sun, RC & Mitchell, RA 2021, 'Lactate supports a metabolic-epigenetic link in macrophage polarization', Science advances, vol. 7, no. 46, eabi8602. https://doi.org/10.1126/sciadv.abi8602

TY - JOUR

T1 - Lactate supports a metabolic-epigenetic link in macrophage polarization

AU - Noe, Jordan T.

AU - Rendon, Beatriz E.

AU - Geller, Anne E.

AU - Conroy, Lindsey R.

AU - Morrissey, Samantha M.

AU - Young, Lyndsay E.A.

AU - Bruntz, Ronald C.

AU - Kim, Eun J.

AU - Wise-Mitchell, Ashley

AU - De Souza Rizzo, Mariana Barbosa

AU - Relich, Eric R.

AU - Baby, Becca V.

AU - Johnson, Lance A.

AU - Affronti, Hayley C.

AU - McMasters, Kelly M.

AU - Clem, Brian F.

AU - Gentry, Matthew S.

AU - Yan, Jun

AU - Wellen, Kathryn E.

AU - Sun, Ramon C.

AU - Mitchell, Robert A.

PY - 2021/11

Y1 - 2021/11

N2 - Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)-induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate- citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage-dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)-driven metabolic-epigenetic link in M2 macrophages.

AB - Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)-induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate- citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage-dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)-driven metabolic-epigenetic link in M2 macrophages.

UR - https://www.scopus.com/pages/publications/85119302595

UR - https://www.scopus.com/inward/citedby.url?scp=85119302595&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abi8602

DO - 10.1126/sciadv.abi8602

M3 - Article

C2 - 34767443

AN - SCOPUS:85119302595

VL - 7

JO - Science advances

JF - Science advances

IS - 46

M1 - eabi8602

ER -

Lactate supports a metabolic-epigenetic link in macrophage polarization

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this