HIF-2α in Resting Macrophages Tempers Mitochondrial Reactive Oxygen Species To Selectively Repress MARCO-Dependent Phagocytosis.
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-2α during other key MΦ 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 immunoprecipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco Concordantly, Hif-2α-/-MΦs 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.
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.|Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Shirley
S
Dehn
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.|Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Matthew
M
DeBerge
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.|Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Xin-Yi
XY
Yeap
INSERM U1065, Centre Mediterraneen de Medecine Moleculaire, Atip-Avenir, 06204 Nice, France.
Laurent
0000-0002-7748-4942
L
Yvan-Charvet
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Deyu
D
Fang
Department of Anesthesiology, University of Colorado, Aurora, CO 80045; and.
Holger K
HK
Eltzschig
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Stephen D
SD
Miller
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; ebthorp@northwestern.edu.|Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Edward B
0000-0003-1387-7058
EB
Thorp
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate; D015847:Interleukin-4 / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015847:Interleukin-4; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C092228:Marco protein, mouse; C495636:Nfe2l2 protein, mouse
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