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 language | English (US) |
|---|---|
| Pages (from-to) | 3639-3649 |
| Number of pages | 11 |
| Journal | Journal of Immunology |
| Volume | 197 |
| Issue number | 9 |
| DOIs | |
| State | Published - Nov 1 2016 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=84992401711&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84992401711&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1600402
DO - 10.4049/jimmunol.1600402
M3 - Article
C2 - 27671111
AN - SCOPUS:84992401711
VL - 197
SP - 3639
EP - 3649
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 9
ER -