Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2

David E. Sanin; Mai Matsushita; Ramon I. Klein Geltink; Katarzyna M. Grzes; Nikki van Teijlingen Bakker; Mauro Corrado; Agnieszka M. Kabat; Michael D. Buck; Jing Qiu; Simon J. Lawless; Alanna M. Cameron; Matteo Villa; Francesc Baixauli; Annette E. Patterson; Fabian Hässler; Jonathan D. Curtis; Christina M. O'Neill; David O'Sullivan; Duojiao Wu; Gerhard Mittler; Stanley Ching Cheng Huang; Erika L. Pearce; Edward J. Pearce

doi:10.1016/j.immuni.2018.10.011

Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2

David E. Sanin, Mai Matsushita, Ramon I. Klein Geltink, Katarzyna M. Grzes, Nikki van Teijlingen Bakker, Mauro Corrado, Agnieszka M. Kabat, Michael D. Buck, Jing Qiu, Simon J. Lawless, Alanna M. Cameron, Matteo Villa, Francesc Baixauli, Annette E. Patterson, Fabian Hässler, Jonathan D. Curtis, Christina M. O'Neill, David O'Sullivan, Duojiao Wu, Gerhard MittlerStanley Ching Cheng Huang, Erika L. Pearce, Edward J. Pearce

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

Abstract

Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψ_m) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψ_m were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψ_m caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψ_m-sensitive transcription factor and Δψ_m as a mediator of mitochondrial-directed nuclear gene expression. Metabolism regulates macrophage activation. Sanin et al. demonstrate that in IL-4-activated macrophages, PGE2 induces changes in the expression of malate-aspartate shuttle genes, which in turn leads to changes in mitochondrial membrane potential and triggers alterations in chromatin accessibility and ETV1-dependent changes in expression of a gene set that includes Retnla.

Original language	English (US)
Pages (from-to)	1021-1033.e6
Journal	Immunity
Volume	49
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2018.10.011
State	Published - Dec 18 2018
Externally published	Yes

Keywords

ETS variant 1
ETV1
IL-4
PGE2
RELMα
immunometabolism
interleukin-4
macrophage
malate-aspartate shuttle
mitochondria
mitochondrial membrane potential
proliferation
prostaglandin E2

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2018.10.011

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Sanin, D. E., Matsushita, M., Klein Geltink, R. I., Grzes, K. M., van Teijlingen Bakker, N., Corrado, M., Kabat, A. M., Buck, M. D., Qiu, J., Lawless, S. J., Cameron, A. M., Villa, M., Baixauli, F., Patterson, A. E., Hässler, F., Curtis, J. D., O'Neill, C. M., O'Sullivan, D., Wu, D., ... Pearce, E. J. (2018). Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2. Immunity, 49(6), 1021-1033.e6. https://doi.org/10.1016/j.immuni.2018.10.011

Sanin, DE, Matsushita, M, Klein Geltink, RI, Grzes, KM, van Teijlingen Bakker, N, Corrado, M, Kabat, AM, Buck, MD, Qiu, J, Lawless, SJ, Cameron, AM, Villa, M, Baixauli, F, Patterson, AE, Hässler, F, Curtis, JD, O'Neill, CM, O'Sullivan, D, Wu, D, Mittler, G, Huang, SCC, Pearce, EL & Pearce, EJ 2018, 'Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2', Immunity, vol. 49, no. 6, pp. 1021-1033.e6. https://doi.org/10.1016/j.immuni.2018.10.011

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title = "Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2",

abstract = "Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression. Metabolism regulates macrophage activation. Sanin et al. demonstrate that in IL-4-activated macrophages, PGE2 induces changes in the expression of malate-aspartate shuttle genes, which in turn leads to changes in mitochondrial membrane potential and triggers alterations in chromatin accessibility and ETV1-dependent changes in expression of a gene set that includes Retnla.",

keywords = "ETS variant 1, ETV1, IL-4, PGE2, RELMα, immunometabolism, interleukin-4, macrophage, malate-aspartate shuttle, mitochondria, mitochondrial membrane potential, proliferation, prostaglandin E2",

author = "Sanin, {David E.} and Mai Matsushita and {Klein Geltink}, {Ramon I.} and Grzes, {Katarzyna M.} and {van Teijlingen Bakker}, Nikki and Mauro Corrado and Kabat, {Agnieszka M.} and Buck, {Michael D.} and Jing Qiu and Lawless, {Simon J.} and Cameron, {Alanna M.} and Matteo Villa and Francesc Baixauli and Patterson, {Annette E.} and Fabian H{\"a}ssler and Curtis, {Jonathan D.} and O'Neill, {Christina M.} and David O'Sullivan and Duojiao Wu and Gerhard Mittler and Huang, {Stanley Ching Cheng} and Pearce, {Erika L.} and Pearce, {Edward J.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.immuni.2018.10.011",

language = "English (US)",

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AU - Sanin, David E.

AU - Matsushita, Mai

AU - Klein Geltink, Ramon I.

AU - Grzes, Katarzyna M.

AU - van Teijlingen Bakker, Nikki

AU - Corrado, Mauro

AU - Kabat, Agnieszka M.

AU - Buck, Michael D.

AU - Qiu, Jing

AU - Lawless, Simon J.

AU - Cameron, Alanna M.

AU - Villa, Matteo

AU - Baixauli, Francesc

AU - Patterson, Annette E.

AU - Hässler, Fabian

AU - Curtis, Jonathan D.

AU - O'Neill, Christina M.

AU - O'Sullivan, David

AU - Wu, Duojiao

AU - Mittler, Gerhard

AU - Huang, Stanley Ching Cheng

AU - Pearce, Erika L.

AU - Pearce, Edward J.

PY - 2018/12/18

Y1 - 2018/12/18

N2 - Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression. Metabolism regulates macrophage activation. Sanin et al. demonstrate that in IL-4-activated macrophages, PGE2 induces changes in the expression of malate-aspartate shuttle genes, which in turn leads to changes in mitochondrial membrane potential and triggers alterations in chromatin accessibility and ETV1-dependent changes in expression of a gene set that includes Retnla.

AB - Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression. Metabolism regulates macrophage activation. Sanin et al. demonstrate that in IL-4-activated macrophages, PGE2 induces changes in the expression of malate-aspartate shuttle genes, which in turn leads to changes in mitochondrial membrane potential and triggers alterations in chromatin accessibility and ETV1-dependent changes in expression of a gene set that includes Retnla.

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KW - RELMα

KW - immunometabolism

KW - interleukin-4

KW - macrophage

KW - malate-aspartate shuttle

KW - mitochondria

KW - mitochondrial membrane potential

KW - proliferation

KW - prostaglandin E2

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SN - 1074-7613

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SP - 1021-1033.e6

JO - Immunity

JF - Immunity

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ER -

Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2

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Keywords

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