HIF-2α in resting macrophages tempers mitochondrial reactive oxygen species to selectively repress MARCO-dependent phagocytosis

Shirley Dehn, Matthew De Berge, Xin Yi Yeap, Laurent Yvan-Charvet, Deyu Fang, Holger K. Eltzschig, Stephen D. Miller, Edward B. Thorp*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Hypoxia-inducible factor (HIF)-α isoforms regulate key macrophage (MΦ) functions during ischemic inflammation. HIF-2α drives proinflammatory cytokine production; however, the requirements for HIF-2a during other key MF functions, including phagocytosis, are unknown. In contrast to HIF-1α, HIF-2α was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2α levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunopre-cipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco. Concordantly, Hif-2α-/- MFs exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2α by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2α can act as a phagocytic repressor. Interestingly, this occurs in resting MΦs through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2α promotes MΦ quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2α suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.

Original languageEnglish (US)
Pages (from-to)3639-3649
Number of pages11
JournalJournal of Immunology
Volume197
Issue number9
DOIs
StatePublished - Nov 1 2016

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Phagocytosis
Reactive Oxygen Species
Macrophages
Interleukin-4
Antioxidants
Cytokines
Immunologic Monitoring
Hypoxia-Inducible Factor 1
Scavenger Receptors
Chromatin
endothelial PAS domain-containing protein 1
Protein Isoforms
Inflammation
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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title = "HIF-2α in resting macrophages tempers mitochondrial reactive oxygen species to selectively repress MARCO-dependent phagocytosis",
abstract = "Hypoxia-inducible factor (HIF)-α isoforms regulate key macrophage (MΦ) functions during ischemic inflammation. HIF-2α drives proinflammatory cytokine production; however, the requirements for HIF-2a during other key MF functions, including phagocytosis, are unknown. In contrast to HIF-1α, HIF-2α was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2α levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunopre-cipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco. Concordantly, Hif-2α-/- MFs exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2α by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2α can act as a phagocytic repressor. Interestingly, this occurs in resting MΦs through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2α promotes MΦ quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2α suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.",
author = "Shirley Dehn and {De Berge}, Matthew and Yeap, {Xin Yi} and Laurent Yvan-Charvet and Deyu Fang and Eltzschig, {Holger K.} and Miller, {Stephen D.} and Thorp, {Edward B.}",
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HIF-2α in resting macrophages tempers mitochondrial reactive oxygen species to selectively repress MARCO-dependent phagocytosis. / Dehn, Shirley; De Berge, Matthew; Yeap, Xin Yi; Yvan-Charvet, Laurent; Fang, Deyu; Eltzschig, Holger K.; Miller, Stephen D.; Thorp, Edward B.

In: Journal of Immunology, Vol. 197, No. 9, 01.11.2016, p. 3639-3649.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HIF-2α in resting macrophages tempers mitochondrial reactive oxygen species to selectively repress MARCO-dependent phagocytosis

AU - Dehn, Shirley

AU - De Berge, Matthew

AU - Yeap, Xin Yi

AU - Yvan-Charvet, Laurent

AU - Fang, Deyu

AU - Eltzschig, Holger K.

AU - Miller, Stephen D.

AU - Thorp, Edward B.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Hypoxia-inducible factor (HIF)-α isoforms regulate key macrophage (MΦ) functions during ischemic inflammation. HIF-2α drives proinflammatory cytokine production; however, the requirements for HIF-2a during other key MF functions, including phagocytosis, are unknown. In contrast to HIF-1α, HIF-2α was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2α levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunopre-cipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco. Concordantly, Hif-2α-/- MFs exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2α by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2α can act as a phagocytic repressor. Interestingly, this occurs in resting MΦs through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2α promotes MΦ quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2α suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.

AB - Hypoxia-inducible factor (HIF)-α isoforms regulate key macrophage (MΦ) functions during ischemic inflammation. HIF-2α drives proinflammatory cytokine production; however, the requirements for HIF-2a during other key MF functions, including phagocytosis, are unknown. In contrast to HIF-1α, HIF-2α was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2α levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunopre-cipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco. Concordantly, Hif-2α-/- MFs exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2α by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2α can act as a phagocytic repressor. Interestingly, this occurs in resting MΦs through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2α promotes MΦ quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2α suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.

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