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.
N1 - Funding Information:
This work was supported by National Institutes of Health Grant R01HL122309 (to E.B.T.); Collaborative Learning and Integrated Mentoring in the Biosciences, Cellular and Molecular Basis of Disease (National Institutes of Health Grant T32 GM08061), and National Institutes of Health Diversity Supplement R01HL122309 (to S.D.); and National Institutes of Health Grants R01DK097075, R01HL092188, R01HL098294, P01IHL114457, and R01HL119837 (to H.K.E.).
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 -